Table 3 The mechanism of macrophage cellular crosstalk in the pathogenesis of PF
Type of crosstalk | Mediator | Mechanism of action | References | |
|---|---|---|---|---|
Macrophage to fibroblast | S100a4 | M2-derived S100a4 promoted mesenchymal progenitor cell fibrogenicity and following fibroblast activation, migration, as well as FMT↑ | ||
CX3CR1 | The downregulation of M2 polarization induced by CX3CL1-CX3CR1 interaction modulate fibrocytes migration and subsequent myofibroblasts activation↓ | [79] | ||
TSLP/MMP9 | Macrophage-derived TSLP/MMP9 promoted the EMT and FMT progress between epithelial cells and fibroblasts↑ | [80] | ||
IL-1/ TGF-β1 | Macrophage-secreted IL-10 regulated M2 polarization via CCL2/CCR2 axis and following fibroblast activation in a TGF-β1 dependent manner↑ | |||
microcystin-LR | Chronic exposure of microcystin-LR suppressed the M2 differentiation by blocking UPRER signaling, thereby inhibiting EMT and FMT↓ | [84] | ||
SPP1/MERTK | Highly proliferation of SPP1hi macrophage contributed to the activation of myofibroblast in PF microenvironment↑ | [85] | ||
ER stress/UPR | The enhancement of ER stress upregulated UPR-associated proteins (IRE1α/ CHOP) to promote M2 polarization and facilitated the TGF-β–mediated myofibroblasts differentiation via PI3K/AKT/mTOR pathway↑ ER stress modified macrophage-fibroblast crosstalk by TLR4 and PINK↑ | |||
miR-142-3p | The delivery of miR-142-3p from macrophage-derived exosomes to fibroblasts can reduce TGFβ-R1 transcript and profibrotic genes expression | [10] | ||
Fibroblast to macrophage | Lactate | Myofibroblast glycolysis relies on lactate to mediate the pathogenic phenotype of alveolar macrophages and induce profibrotic mediator expression in macrophages↑ | ||
Fatty acid | Dysfunctional fatty acid metabolism in fibroblasts promoted the secretion of PPAR-γ to activate M2 polarization and subsequent phenotypes switch between lipofibroblasts and myofibroblasts↑ | |||
Macrophage to AEC | IL-4/IL-13 | IL-4/IL-13 induced M2 cell culture media promoted the expression of fibrotic factors and antiapoptotic meditators (COX, BCL2) in ATII cells↑ | [108] | |
NOX2 | M2 macrophage stimulated the senescence of AECs in a NOX2 dependent manner via increasing superoxide production↑ | [109] | ||
PI3K/Akt | Macrophage-secreted cytokine levels are involved in the activation of EMT process through PI3K/Akt signaling↑ | [110] | ||
Keratin 8 | Keratin 8 prohibited macrophage-induced transitional AEC senescence from bleomycin exposure by decreasing macrophage fibrotic cytokines↓ | [111] | ||
STING | The blocking of STING signaling inhibited M1 polarization and fibrotic response within the co-culture system of macrophages, fibroblasts and AECs↓ | [112] | ||
AEC to macrophage | CCL2/CCL12 | AEC-induced CCL2/CCL12 expression recruited monocyte-oriented macrophages within fibrotic microenvironment↑ Senescent AECs promoted Ly6C monocytes to migrate and differentiate into IMs via CCL2↑ | ||
AEC to macrophage | GM-CSF | Expression of GM-CSF in ATII cells would switch on the differentiation of fetal AMs, and the absence of ATII-derived Csf2 led to AM population atrophy↑ | [116] | |
PAI-1 | The deletion of PAI-1 in senescent ATII cells inhibited the secretion of SASP and subsequent M2 polarization↑ | [117] | ||
miR-92a-3p | miR-92a-3p in AEC-derived exosomes could be absorbed by AMs to induce inflammatory cytokines↑ | [118] | ||
Ninj1 | Upregulation of Ninj1 in AECs boosted the activation of macrophage within PF microenvironment↑ | [119] | ||
Shh | Shh secreted by ATII cells promoted the alternative activation of osteopontin-mediated M2 macrophage↑ | [120] | ||
12-LOX | Senescent ATII cells may facilitate macrophage to polarize into preferential M2 type via 12-LOX dependent pathway in PF microenvironment↑ | [121] | ||