Macrophages in Systemic Lupus Erythematous (SLE)
Innate Immunity and SLE
Systemic Lupus Erythematous (SLE) is a chronic debilitating and autoimmune disease that can influence a lot of organs such as kidneys, brain, joints, and skin. The hallmarks of SLE include chronic inflammation and the production of many kinds of autoantibodies to self-antigens. Autoantibodies circulate in the body, deposit into tissues, and contribute to tissue damage, leading to pathology. Evidence links the profound defects in innate immunity with SLE disease initiation and progression, as well as with tissue damage. Defective phenotypes and functions of neutrophils, dendritic cells, monocytes, and macrophages have been recognized in SLE patients. These defects play vital functions in the pathogenesis of SLE, including ineffective apoptotic debris clearance, self-antigen presentation, and inflammatory cytokine production.
The Roles of Macrophages in SLC
Abnormalities in cell death have been demonstrated in patients with SLE, including enhanced apoptosis, necrosis, and autophagy. Macrophages from SLE patients show defects in the clearance of apoptotic cells (ACs). The ACs uncleared efficiently may release autoantigens and activate the autoreactive B cells, resulting in loss of tolerance to autoantigens as well as production of autoantibodies. Then the resultant immune complex (IC) deposition causes tissue injuries in different organs affected. In addition, Type I interferon (IFN) can induce plasma cells to produce more autoantibodies and inhibit the clearance of ACs by macrophages. Moreover, macrophages have well-developed secretory functions and serve as an important source for a variety of cytokines, by which macrophages participate in inflammation and the modulation of adaptive immunity.
Fig.1 Possible mechanism of macrophage polarization in SLE. (Ahamada, 2021)
Polarization of Macrophages in SLE
Macrophages can be classified as, but not limited to, classically-activated M1 (infiltrating and inflammatory) macrophages and alternatively-activated M2 (tissue-resident and trophic) macrophages. Studies have shown different functions for M1 and M2 macrophages in SLE. The process of monocyte-to-macrophage differentiation contributes to SLE pathogenesis, possibly by polarizing macrophages towards classic M1 activation. M1 macrophages promote tissue damage, while M2 macrophages participate in tissue healing in SLE. Adoptive transplantation of M2, but not M1 macrophages significantly ameliorated SLE disease activity.
Type I Interferon and Macrophage Function
Type I IFN has been considered as the central pathogenic cytokine in SLE development. Plasmacytoid dendritic cells (pDCs) are capable of producing massive amounts of type I IFNs upon stimulation. Furthermore, TREM-like transcript 4 (TREML4) may potentiate toll-like receptor 7 (TLR7) signaling and type I IFN production in macrophages. Type I IFNs can induce the formation of neutrophil extracellular traps, which are a source of self-stimuli and reciprocally enhance the production of type I IFNs. Type I IFN can induce plasma cells to produce more autoantibodies and inhibit the clearance of ACs by macrophages.
Therapies of Targeting Macrophages in MS
SLE is characterized by widespread inflammation in connective tissues, and it has no known cure. As a result of the important and deterministic roles in both health and disease, macrophages have gained considerable attention for therapy of SLE.
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Blocking recruitment of monocytes and macrophage activation by targeting the colony-stimulating factor (CSF-1)/CSF-1 receptor signaling axis, C-X-C motif chemokine receptor 9 (CXCR9), and Bruton's tyrosine kinase.
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Modulation of macrophages. 1) Induction of M2 macrophage polarization and the production of anti-inflammatory cytokines by pioglitazone, the aryl hydrocarbon receptor (AhR)-mediated signaling pathway and expression of peroxisome proliferators-activated receptors (PPARγ); 2) inhibition of M1 inflammatory phenotypes in vitro by sodium valproate, a histone deacetylase (HDAC) inhibitor.
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Promoting clearance of ACs by macrophages via PPARs and liver X receptors.
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Reference
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Ahamada, M.; et al. Macrophage polarization and plasticity in systemic lupus erythematosus. Frontiers in Immunology. 2021, 12.
