Skip to main content

Syncytium calcium signaling and macrophage function in the heart

Abstract

Macrophages are traditionally viewed as a key component of the immunity defense system. Recent studies have identified resident macrophages in multiple organs including the heart, in which the cells perform their crucial role on tissue repair after myocardial infarction (MI). The cardiac-specific macrophages interdigitate with cardiomyocytes particularly at the atrioventricular node region. The integrative communication between macrophage and cardiomyocytes can modulate the contractile function of the heart. Coordinated control of intracellular calcium signaling and intercellular electrical conduction via the syncytium network underlie the synchronized beating of the heart. In this review article, we introduce the concept the syncytium calcium signaling in the cardiomyocytes can modulate gene expression in the resident macrophages and their integration with the cardiomyocytes. The cardiac macrophages originate from bone marrow stem cells, migrate to local via vessel, and settle down as a naturalization process in heart. As the macrophages perform on regulating electrical conduction, and accomplish post MI non-scared completed regeneration or partial regeneration with fibrotic scar at different stage of postnatal development, we understand that multiple functions of cardiac macrophage should carry on with diverse linages. The naturalization process in heart of macrophages to the cardiomyocytes serves important roles to control of electrical signaling and calcium-dependent contractile function of the heart.

Introduction

As a major component in the first line of immunity defense, macrophages are distributed in almost every tissues, including cardiac macrophages in the heart, cerebellum microglia cells in the brain, hepatic Kupffer cells in the liver, alveolar macrophages in the lungs, and Langerhans cells in the epidermis. Although macrophage functions in the immune system have been investigated extensively [1,2,3], the tissue-specific functions of macrophages in the heart are largely unknown. As the ATM/mTOR signaling, Rac1-GTPase, and PI3 K/AKT pathways play critical roles in controlling migration of cell [1,2,3,4], the multiple cell surface antigens such as CCR2/CD192, CD64/FcγR1, CX3CR1 and Mac3 were linked to origination of monocyte-macrophage differentiation and polarization in post myocardial infarction (MI) [5,6,7,8,9], but the molecular basis of macrophages migrating into specific tissues under physiological or pathological conditions, and fundamental knowledge of cell–cell recognition are much more obscure.

The cardiac macrophages developed from bone marrow stem cells (plus spleen stem cells as well in mouse), migrated through cardiac vessel from circulated blood, and settled down with polarization in heart could comprehend as a naturalization process in heart. The macrophages play crucial role on regulating electrical conduction by associating with AV node [10], and they are also critical for post MI repair and recovering of cardiac function after MI. This macrophage associated repair would be accomplished with no-scard completed regeneration in neonatal heart or with a partial regeneration with fibrotic scar after P7 [5, 6]. The cardiac macrophages could perform diverse functions on promoting stem cell-cardiomyocyte regeneration and angiogenesis with different cell linages. Here we propose that control of intracellular calcium signaling contributes to the naturalization process of macrophages in the heart and to modulating the contractile function of the cardiomyocytes in the context of a syncytium network.

Macrophages facilitate cardiac electrical conduction and promote cardiac regeneration

A recent study by Hulsmans et al. showed that resident macrophages were enriched in human and mouse atrioventricular (AV) node and can regulate the electrophysiological activity of cardiomyocytes through the gap-junction protein, connexin 43 (Cx43), at the “linking” portion of the conducting cardiomyocyte and the macrophage [10, 11]. This pilot study reveals the critical role of tissue-specific macrophages that has never before been recognized in cardiac function, and raises many interesting research subjects about the physiological and pathological bases of human cardiovascular diseases.

Using GFP labelled cardiac macrophages, cardiomyocytes located in the lower nodal or AV bundle were frequently interspersed with macrophages that have an elongated, spindle-shaped appearance [12, 13]. These macrophages longitudinally distribute along the AV-His bundle, with their cytoplasmic portion extending and reaching cardiomyocytes across long distances [10] (Fig. 1).

Fig. 1
figure 1

Sketch of the association between resident macrophage and cardiomyocytes in the heart. Cardiomyocytes are aligned longitudinally in the heart (a) with actin-myosin apparatus and carry contraction controlled by CICR (b). Resident macrophages are naturalized in cardiac tissue (c). Through connexin 43 and other integrated and extracellular matrix proteins, resident macrophages facilitate conducting cardiomyocytes and modify the action potential of cardiomyocytes (d)

In heart tissue, Cx43 is located on the intercalated discs responsible for electrical conduction through neighboring cardiomyocytes, and is essential for the synchronized contraction of the heart. The Cx43-mediated cell–cell linkage provides the connection between resident macrophages and cardiomyocytes [10] and forms the structural framework to couple these two types of cells along with extracellular matrix. Such connection complex could guarantee synchronization of cardiomyocyte contraction and its control by the resident macrophages at the AV His-bundle in the heart.

Although more detailed information on the mechanisms of how resident macrophages facilitate the conduction system in the heart remained to be explored, the physiological function of the macrophages on maintaining AV conduction were supported by several animal model studies where AV blocks were introduced through loss-of-function investigations. With deletion of Cx43 in the macrophages, the Cx3cr1 Cx43/ mice developed severe 1st degree and 2nd degree AV block. With CSF1 deletion in the macrophages, the CSF1op mice could develop non-matured macrophages with a lack of normal function and exhibited 1st degree and 2nd degree AV block. Deletion of macrophage Cd11b [12, 14] in the Cd11bDTR mice produced 1st degree, 2nd degree, and even life threatening 3rd degree AV block [10]. These three experiments proved the function of the cardiac resident macrophages on maintaining normal conduction in the heart.

The recent study by Hulsmans et al. [10] revealed that the external macrophage can bond to the conducting cardiomyocyte in AV node to regulate the electrophysiological activity of the heart via the gap-junction protein, connexin 43 (Cx43). However, before this discovery, the most researches mainly focused on the repair function of macrophages recruited from blood flow circulating [6, 15, 16, 17]. After MI, circulated monocyte-macrophages were recruited by the infarct zone, and then the naturalizing cells play their critical function on cleaning apoptotic death clashes and promoting cardiac stem cell to regenerate cardiomyocyte. Among those studies, the neonatal repair in 7 day post MI revealed an interesting phenomenon that on P7 neonatal heart, the post MI repair carried by macrophages generated no-scar healing. After P7, the repair could perform a partial regeneration and generate fibrotic scar in the MI zone [6]. Severe difficulty on the completed regeneration post MI was detected within the cardiac macrophage knockout animals. These data suggest the critical roles of the resident cardiac macrophage on cardiomyocytes and angiogenesis [6]. We would like to emphasize that more investigation on this no-scar regeneration in this timing frame could provide us more opportunities to unveil detailed molecular mechanism of the naturalization from circulated cell to resident cardiac macrophage through migration and polarization within the heart early development.

Surface antigens reflect functional complexity of cardiac macrophages

Rationally, cell surface antigens on specified macrophages would be critical for the cell migration, polarization summarized as naturalization in heart although the related molecular mechanisms are still under investigation. These cardiac macrophage antigens plus intracellular markers of the cell are utilized biomarkers for us to discover function of macrophages in cardiac tissues. The cell surface antigens distribute on monocyte-macrophage include CCR2/CD192, CD64/FcγR1, CX3CR1 and Mac3 [5,6,7,8,9]. Some macrophage specific antigens are also distributed in macrophage cytoplasmic location within endosomal/lysosomal compartment, or secreted to extracellular microenvironment along with their cell surface distribution. The representative antigens in this category are CD68/macrosialin, CD163 and Galectin 3/Mac2 [5, 18, 19].

In adult mammals, cardiac macrophages origin from their bone marrow as well as spleen in mouse. While how macrophages differentiating from monocyte during embryonic development is still a mystery (discussed below), many information are discovered from myocardial infarction mouse model. For tracking the macrophage differentiation and settlement in heart after MI, many gating strategies employed with combined different antigens. The combination Ly6ChighCCR2highCX3CR1lowCD62 L+ used to examines classical monocytes [20], and MHCIIlowCCR2+ and Lineage−CD11 b+F4/80lowLy6C+ for cardiac monocyts in mouse model [21, 22]. The CD45+CD11 b+F4/80+CD206− and CD4+CD11 b+F4/80+CD206+ used to detect mouse classic M1 and M2 macrophage [23], and CD45+CD11 b+F4/80+Ly6Clow for Resident cardiac macrophages [22]. The CD45+F4/80+MHC-IIlowCCR2− and CD45+F4/80+MHC-IIhighCCR2− is routine representative for cardiac resident macrophages [6, 22]. Many others were developed for investigating the mechanism of diverse function of macrophage function in heart.

Syncytium calcium signaling underlies synchronized contractile activity of the heart

Synchronized contractile function of the heart is essential to life. Exactly how resident macrophages in the heart evolved as a fail-safe way to guarantee robust cardiac output under physiological and pathological conditions remains an important area of research.

Calcium (Ca) ions are important second messengers modulating many cellular functions. In the heart, entry of extracellular Ca via Ca channels located on the plasma membrane triggers opening of the ryanodine receptor (RyR) located in the sarcoplasmic reticulum (SR) through Ca-induced Ca release (CICR) [24,25,26,27]. The elementary units of Ca release from SR in cardiomyocytes are discreet, localized events known as Ca sparks. Ca sparks are quantal Ca release events that originate from paracrystalline arrays of RyR channels on the SR surface [13, 14, 24]. The discovery of Ca sparks has revolutionized understanding of the physiology and pathophysiology of Ca signaling in the heart.

Synchronized elevation of intracellular Ca triggers contraction of the actin-myosin apparatus by diastolic depolarization, and the crosstalk of electrical conduction between neighboring cardiomyocytes via the interconnection of their intercalated discs through the connexin complex. Longitudinal flow of Ca signaling via the syncytium network characterizes the heart as an efficient circulation pump.

Macrophage functions in calcium-dependent manner

Although we normally consider that macrophages function as cells in the front line of the immune system, these macrophages also play critical roles in many other aspects, including cardiac electrical activity, wound repair, embryonic development, and many more [1,2,3]. All these roles can be categorized into three biological processes: migration, endocytosis and phagocytosis. Cytoskeletal regulated migration drives cell movements in tissues and through endothelial cells to their final destinations, where they will carry out functions involved with Capg, Mpp1, Myo1f, Myo5a and Wip1 [4, 27,28,29]. Endocytosis accomplished by macrophages is a receptor-mediated uptake process for liquids [30]. The internalized materials will interact with diverse receptors such as Alcam, CD9, CD84, Mamdac2, Itgfg3 and Lgals, and are then degraded rapidly after lysosomal fusion. Phagocytosis as a first defense against pathogen attack is defined as the uptake for solid particles about a few micrometer in diameter. Phagocytosis involves recognition of endocytic receptors, vesicle trafficking and protein degradation, carbohydrate/lipid/DNA digestion and many other processes [4, 31,32,33]. It is obvious that cell surface antigens are important for all three processes, whether for the cells to execute their tasks, or to distinguish which protocol to initiate.

Recent research demonstrated that Ca may contribute to modulation of gene expression in the macrophage. Using monocyte-derived macrophages (MDMs) from patients with chronic obstructive pulmonary disease (COPD), Provost et al. showed that extracellular Ca could enhance phagocytosis and cytokine secretion associated with IL-8, TNF-α, and macrophage inflammatory protein (MIP) subunits MIP-1a and MIP-1b [34]. Additionally, the bacterial challenge of MDMs increased cell surface expression of bacterial recognition receptors, CD16 and MARCO, which led to increased recognition by the macrophage to more potential pathogens, initiating more phagocytosis. This study provides the base for the therapeutic use of Ca to increase macrophage phagocytosis and decrease chronic bacterial infection [34]. It appears that the expression patterns of cell membrane integrated proteins are critical factors that determine how the cells behave (Table 1). Thus, delineating the communication between extracellular Ca homeostasis with intracellular Ca signaling represents an important area of investigation for the tissue-specific function of macrophages.

Table 1 Calcium related gene expression and macrophage functions

Extracellular Ca influxes through plasma membrane Ca channels take the responsibility for the cytoplasmic phagosomal oxidative reaction and inflammatory cytokine reaction [29, 40, 42]. When specific Ca channel inhibitors were applied, cytokine secretion by Ca-mediated endocytosis were inhibited [34]. The immune effectiveness can be improved with elevation of extracellular Ca concentrations in the range of physiologic levels of Ca signaling [46, 47]. In vitro studies with macrophage-like cell lines U937 and MH-S [48] demonstrated that macrophage recognition to elevated Ca involves a sensor zone on the carbohydrate chains of CD43 [49].

Although the Ca-dependent manner of macrophage function was discovered in monocyte-derived macrophages or macrophage-like U937 and MH-S cells, it is possible that the resident macrophages would behavior according to Ca levels in the micro-environment of their niche in the heart tissue.

Development and differentiation of macrophages require colony-stimulating factor

Macrophages are developed and differentiated from the mononuclear phagocyte system (MPS) [3, 50]. While myeloid progenitor/granulocytes develop to monoblasts, promonocytes and then monocytes migrate into specific tissues, colony-stimulating factors (CSF) can direct differentiation of MPS. These CSFs include macrophage CSF (CSF-1), granulocyte macrophage (GM-CSF) and fms-like tyrosine kinase 3 ligand (Flt3-ligand) [51,52,53]. The development and differentiation of tissue-specific resident macrophages have many distinct pathways in both normal development and pathological progress.

The characteristics of macrophages with deletion of CSF-1 in the mouse model pinpoint many critical functions of macrophages in somatic differentiation and the development of the pancreas and nervous system in mammal [53, 54]. Genetic ablation of CSF-1 in mice produced infertility in both males and females due to macrophages failing to adapt to the indigenous tissue and failing to settle down as resident macrophage to build the necessary functional architecture of primary reproduction organs and tissues. Resident macrophages are critical in adult individuals and even more imperative during the differentiation process in mouse embryos. This crucial function of macrophages during animal development also contributes to the configuration of the conduction system in the heart [10].

The mononuclear phagocyte lineage differentiating progress is under the control of macrophage CSF, however, no research has reported the direct involvement of Ca signaling with CSF. An earlier data revealed that the concentration of cytosolic Ca pre-incubated with granulocyte–macrophage CSFs can effectively activate an oxidative burst of granulocytes measured with the production of intracellular superoxide (O2) anions [55]. Release of Ca-containing crystals could change extracellular Ca in the micro-environment and potentially enhance macrophage CSF-mediated osteoclastogenesis [56]. These data demonstrate the possibility that CSF plus Ca could re-pattern cell membrane integrated proteins [34]. It is possible that the micro-environment Ca could affect CSF function during tissue settlement of macrophages in organogenesis along with other type of cells.

Prospect: Ca dependence could be a mechanism of MPS-to-resident macrophage in heart

In the heart, CICR and syncytium cell–cell communication underlie the synchronized contractions of the cardiomyocytes to drive blood circulation throughout the entire body (Fig. 1a, b). Electrical impulses are carried longitudinally through cardiomyocytes linked by N-cadherin, connexins, and other associated proteins [57, 58] (Fig. 1d). As discussed above, resident macrophages can facilitate this electrical conduction within the AV node [10]. If these is any lineage-tracing data to classify the role of resident cardiac macrophages is the valuable question we have to clear in future investigation, the answer could be mysterious up-to-date. As we discussed, more than 30 surface proteins involve in the functional differentiation from blood monocyte to cardiac monocyte, and from circulated macrophage to resident cardiac macrophage. Meanwhile, the P7 non-scar regeneration and conducting signal promotion by macrophages enlighten that multiple lineage of macrophages could exist for these divers functions.

The concept of resident macrophages facilitating electrical conduction in the heart raises many interesting subjects that should be explored further about the role of macrophages in other cardiac functions such as how pre-mononuclear phagocytes differentiate along with conducting cardiomyocytes, what principle role they play during co-developmental architecture, how these resident macrophages function in adult heart, what maintains their role in continuous contracting tissue as a non-contractile cells, and whether anchoring proteins and extracellular matrix proteins are required to direct and connect resident macrophage to conducting cardiomyocyte.

It should not be a coincidence that there is both a Ca-dependency of macrophages and CICR dependency of cardiomyocytes for contraction. The intracellular Ca in both cells should provide coordination for their integration, and the extracellular Ca should provide a micro-environment for homeostasis. The syncytium Ca signaling would allow for a more efficient macrophage niche within the cardiomyocytes and consequently for the synchronized contraction of the heart.

Abbreviations

AV:

atrioventricular

CSF:

colony-stimulating factor

MPS:

mononuclear phagocyte system

GM-CSF:

granulocyte macrophage

CX43:

connexin 43

Ca:

calcium

RyR:

ryanodine receptor

SR:

sarcoplasmic reticulum

CICR:

Ca-induced Ca release

COPD:

chronic obstructive pulmonary disease

MDM:

monocyte-derived macrophage

MIP:

macrophage inflammatory protein

MI:

myocardial infarction

References

  1. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496(7446):445–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Park I, Kassiteridi C, Monaco C. Functional diversity of macrophages in vascular biology and disease. Vascul Pharmacol. 2017;S1537–1891(17):30305-1.

    Google Scholar 

  3. Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, et al. Development of monocytes, macrophages, and dendritic cells. Science. 2010;327(5966):656–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tang Y, Pan B, Zhou X, Xiong K, Gao Q, et al. Wip1-dependent modulation of macrophage migration and phagocytosis. Redox Biol. 2017;13:665–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ma Y, Mouton AJ, Lindsey ML. Cardiac macrophage biology in the steady-state heart, the aging heart, and following myocardial infarction. Transl Res. 2018;191:15–28.

    Article  PubMed  Google Scholar 

  6. Aurora AB, Porrello ER, Tan W, Mahmoud AI, Hill JA, et al. Macrophages are required for neonatal heart regeneration. J Clin Investig. 2014;124(3):1382–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tsou CL, Peters W, Si Y, Slaymaker S, Aslanian AM, et al. Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. J Clin Investig. 2007;117:902–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. De Calisto J, Villablanca EJ, Mora JR. FcgammaRI (CD64): an identity card for intestinal macrophages. Eur J Immunol. 2012;42:3136–40.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Mittal R, Sukumaran SK, Selvaraj SK, Wooster DG, Babu MM, et al. Fcgamma receptor I alpha chain (CD64) expression in macrophages is critical for the onset of meningitis by Escherichia coli K1. PLoS Pathog. 2010;6:e1001203.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hulsmans M, Clauss S, Xiao L, Aguirre AD, King KR, et al. Macrophages facilitate electrical conduction in the heart. Cell. 2017;169(3):510–22.

    Article  CAS  PubMed  Google Scholar 

  11. Biel M, Wahl-Schott C, Michalakis S, Zong X. Hyperpolarization-activated cation channels: from genes to function. Physiol Rev. 2009;89(3):847–85.

    Article  CAS  PubMed  Google Scholar 

  12. Heidt T, Courties G, Dutta P, Sager HB, Sebas M, et al. Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction. Circ Res. 2014;115(2):284–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Molawi K, Wolf Y, Kandalla PK, Favret J, Hagemeyer N, et al. Progressive replacement of embryo-derived cardiac macrophages with age. J Exp Med. 2014;211(11):2151–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cecchini MG, Dominguez MG, Mocci S, Wetterwald A, Felix R, et al. Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. Development. 1994;120(6):1357–72.

    CAS  PubMed  Google Scholar 

  15. Frantz S, Nahrendorf M. Cardiac macrophages and their role in ischaemic heart disease. Cardiovasc Res. 2014;102(2):240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sager HB, Hulsmans M, Lavine KJ, Beltrami Moreira MB, Heidt T, et al. Proliferation and recruitment contribute to myocardial macrophage expansion in chronic heart failure. Circ Res. 2016;119(7):853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ishikawa S, Noma T, Fu HY, Matsuzaki T, Ishizawa M, et al. Apoptosis inhibitor of macrophage depletion decreased M1 macrophage accumulation and the incidence of cardiac rupture after myocardial infarction in mice. PLoS ONE. 2017;12(11):e0187894.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Molawi K, Wolf Y, Kandalla PK, Favret J, Hagemeyer N, et al. Progressive replacement of embryo-derived cardiac macrophages with age. J Exp Med. 2014;211:2151–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Engel DR, Krause TA, Snelgrove SL, Thiebes S, Hickey MJ, et al. CX3CR1 reduces kidney fibrosis by inhibiting local proliferation of profibrotic macrophages. J Immunol. 2015;194:1628–38.

    Article  CAS  PubMed  Google Scholar 

  20. Nahrendorf M, Swirski FK. Monocyte and macrophage heterogeneity in the heart. Circ Res. 2013;112:1624–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lavine KJ, Epelman S, Uchida K, Weber KJ, Nichols CG, et al. Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart. Proc Natl Acad Sci USA. 2014;111:16029–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Heidt T, Courties G, Dutta P, Sager HB, Sebas M, et al. Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction. Circ Res. 2014;115:284–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yan X, Anzai A, Katsumata Y, Matsuhashi T, Ito K, et al. Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction. J Mol Cell Cardiol. 2013;62:24–35.

    Article  CAS  PubMed  Google Scholar 

  24. Cheng H, Lederer WJ. Calcium sparks. Physiol Rev. 2008;88(4):1491–545.

    Article  CAS  PubMed  Google Scholar 

  25. Zalk R, Marks AR. Ca2+ release channels join the ‘resolution revolution’. Trends Biochem Sci. 2017;42(7):543–55.

    Article  CAS  PubMed  Google Scholar 

  26. Garcia MI, Boehning D. Cardiac inositol 1,4,5-trisphosphate receptors. Biochim Biophys Acta. 2017;1864(6):907–14.

    Article  CAS  PubMed  Google Scholar 

  27. Martí-Lliteras P, Regueiro V, Morey P, Hood DW, Saus C, et al. Nontypeable Haemophilus influenzae clearance by alveolar macrophages is impaired by exposure to cigarette smoke. Infect Immun. 2009;77(10):4232–42.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hackam DJ, Rotstein OD, Schreiber A, Zhang WJ, Grinstein S. Rho is required for the initiation of calcium signaling and phagocytosis by Fcgamma receptors in macrophages. J Exp Med. 1997;186(6):955–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Link TM, Park U, Vonakis BM, Raben DM, Soloski MJ, et al. TRPV2 has a pivotal role in macrophage particle binding and phagocytosis. Nat Immunol. 2010;11(3):232–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Doherty GJ, McMahon HT. Mechanisms of endocytosis. Annu Rev Biochem. 2009;78:857–902.

    Article  CAS  PubMed  Google Scholar 

  31. Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol. 2009;21(4):317–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11(5):373–84.

    Article  CAS  PubMed  Google Scholar 

  33. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140(6):805–20.

    Article  CAS  PubMed  Google Scholar 

  34. Provost KA, Smith M, Arold SP, Hava DL, Sethi S. Calcium restores the macrophage response to nontypeable haemophilus influenzae in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2015;52(6):728–37.

    Article  CAS  PubMed  Google Scholar 

  35. Tauseef M, Knezevic N, Chava KR, Smith M, Sukriti S, et al. TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation. J Exp Med. 2012;209(11):1953–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Steinckwich N, Schenten V, Melchior C, Brechard S, Tschirhart EJ. An essential role of STIM1, Orai1, and S100A8–A9 proteins for Ca2+ signaling and FcγR-mediated phagosomal oxidative activity. J Immunol. 2011;186(4):2182–91.

    Article  CAS  PubMed  Google Scholar 

  37. Kelly EK, Wang L, Ivashkiv LB. Calcium-activated pathways and oxidative burst mediate zymosan-induced signaling and IL-10 production in human macrophages. J Immunol. 2010;184(10):5545–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Xu S, Huo J, Gunawan M, Su IH, Lam KP. Activated dectin-1 localizes to lipid raft microdomains for signaling and activation of phagocytosis and cytokine production in dendritic cells. J Biol Chem. 2009;284(33):22005–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Xu S, Huo J, Lee KG, Kurosaki T, Lam KP. Phospholipase Cgamma2 is critical for dectin-1–mediated Ca2+ flux and cytokine production in dendritic cells. J Biol Chem. 2009;284(11):7038–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yamamoto S, Shimizu S, Kiyonaka S, Takahashi N, Wajima T, et al. TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nat Med. 2008;14(7):738–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Savignac M, Mellstrom B, Naranjo JR. Calcium-dependent transcription of cytokine genes in T lymphocytes. Pflugers Arch. 2007;454(4):523–33.

    Article  CAS  PubMed  Google Scholar 

  42. TranVan Nhieu G, Clair C, Grompone G, Sansonetti P. Calcium signalling during cell interactions with bacterial pathogens. Biol Cell. 2004;96(1):93–101.

    Article  CAS  PubMed  Google Scholar 

  43. Hanley PJ, Musset B, Renigunta V, Limberg SH, Dalpke AH, et al. Extracellular ATP induces oscillations of intracellular Ca2+ and membrane potential and promotes transcription of IL-6 in macrophages. Proc Natl Acad Sci USA. 2004;101(25):9479–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cuschieri J, Gourlay D, Garcia I, Jelacic S, Maier RV. Slow channel calcium inhibition blocks proinflammatory gene signaling and reduces macrophage responsiveness. J Trauma. 2002;52(3):434–42.

    CAS  PubMed  Google Scholar 

  45. Hishikawa T, Cheung JY, Yelamarty RV, Knutson DW. Calcium transients during Fc receptor–mediated and nonspecific phagocytosis by murine peritoneal macrophages. J Cell Biol. 1991;115(1):59–66.

    Article  CAS  PubMed  Google Scholar 

  46. Duvoix A, Mackay RM, Henderson N, McGreal E, Postle A, et al. Physiological concentration of calcium inhibits elastase-induced cleavage of a functional recombinant fragment of surfactant protein D. Immunobiology. 2011;216(1–2):72–9.

    Article  CAS  PubMed  Google Scholar 

  47. Cooley J, McDonald B, Accurso FJ, Crouch EC, Remold-O’Donnell E. Patterns of neutrophil serine protease–dependent cleavage of surfactant protein D in inflammatory lung disease. J Leukoc Biol. 2008;83(4):946–55.

    Article  CAS  PubMed  Google Scholar 

  48. Diler E, Schwarz M, Nickels R, Menger MD, Beisswenger C, et al. Influence of external calcium and thapsigargin on the uptake of polystyrene beads by the macrophage-like cell lines U937 and MH-S. BMC Pharmacol Toxicol. 2014;15:16.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Miki Y, Oguri E, Hirano K, Beppu M. Macrophage recognition of cells with elevated calcium is mediated by carbohydrate chains of CD43. Cell Struct Funct. 2013;38(1):43–54.

    Article  CAS  PubMed  Google Scholar 

  50. Hume DA, MacDonald KP. Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood. 2012;119(8):1810–20.

    Article  CAS  PubMed  Google Scholar 

  51. Hume DA, Ross IL, Himes SR, Sasmono RT, Wells CA, et al. The mononuclear phagocyte system revisited. J Leukoc Biol. 2002;72(4):621–7.

    CAS  PubMed  Google Scholar 

  52. Pollard JW. Trophic macrophages in development and disease. Nat Rev Immunol. 2009;9(4):259–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD, et al. Macrophage receptors and immune recognition. Annu Rev Immunol. 2005;23:901–44.

    Article  CAS  PubMed  Google Scholar 

  54. Gow DJ, Sester DP, Hume DA. CSF-1, IGF-1, and the control of postnatal growth and development. J Leukoc Biol. 2010;88(3):475–81.

    Article  CAS  PubMed  Google Scholar 

  55. Sullivan R, Fredette JP, Griffin JD, Leavitt JL, Simons ER, et al. An elevation in the concentration of free cytosolic calcium is sufficient to activate the oxidative burst of granulocytes primed with recombinant human granulocyte-macrophage colony-stimulating factor. J Biol Chem. 1989;264(11):6302–9.

    CAS  PubMed  Google Scholar 

  56. Chang CC, Tsai YH, Liu Y, Lin SY, Liang YC. Calcium-containing crystals enhance receptor activator of nuclear factor κB ligand/macrophage colony-stimulating factor-mediated osteoclastogenesis via extracellular-signal-regulated kinase and p38 pathways. Rheumatology (Oxford). 2015;54(10):1913–22.

    Article  CAS  Google Scholar 

  57. Soh BS, Buac K, Xu H, Li E, Ng SY, Chmielowiec J, Jiang X, Bu L, Li RA, Cowan C, Chien KR, et al. N-cadherin prevents the premature differentiation of anterior heart field progenitors in the pharyngeal mesodermal microenvironment. Cell Res. 2014;24(12):1420–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Desplantez T. Cardiac Cx43, Cx40 and Cx45 co-assembling: involvement of connexins epitopes in formation of hemichannels and Gap junction channels. BMC Cell Biol. 2017;18(Suppl 1):3.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Authors’ contributions

XHX conceived of the study. ZX, ZL and WXF collected and analyzed the data. XHX, ZX, ZL, WXF EC, JW, FC, TT, SC, OJ, HT, JB and JM prepared the manuscript and all authors edited the manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

Not applicable.

Consent for publication

Not applicable.

Ethics approval and consent to participate

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Funding and acknowledgements

This work was supported by the National Natural Science Foundation of China (#31371256/31571273/31771277), the Ministry of Science and Technology of China (#2015CB943100), the National Department of Education Central Universities Research Fund (#GK20130100/201701005/GERP-17-45), US Maryland Stem Cell Research Fund (2009MSCRFE008300), the Foreign Distinguished Scientist Program from the National Department of Education (#MS2014SXSF038), and the Outstanding Doctoral Thesis fund (#X2014YB02/X2015YB05).

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xuehong Xu.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, X., Li, Z., Wang, Z. et al. Syncytium calcium signaling and macrophage function in the heart. Cell Biosci 8, 24 (2018). https://doi.org/10.1186/s13578-018-0222-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13578-018-0222-6

Keywords