Macrophages in Autoimmune Diseases

The immune system can defend the body against internal and external damages by promoting inflammatory processes. However, inflammation can also be potentially harmful to the body. In many autoimmune diseases, the presence of autoantibodies and autoreactive B and T cells indicates that the adaptive immune system is critical for pathogenesis, but this cannot fully account for the development of autoimmune diseases, and the innate immune response may play a necessary and irreplaceable role as well. Many autoimmune diseases are characterized by high levels of macrophage infiltration. Macrophages are involved in inflammatory stimuli, including autoimmunity. Therefore, the comparison regarding the contribution of macrophages to the pathogenesis between representative autoimmune diseases would be important for understanding the cellular mechanisms of the onset or development of autoimmune diseases, specifically in the context of rheumatoid arthritis (RA), inflammatory bowel diseases (IBD), multiple sclerosis (MS), systemic lupus erythematous (SLE), and type 1 diabetes (T1D).

Macrophage Polarization in Autoimmune Diseases

Macrophages infiltration is generally observed in many autoimmune diseases. Characteristic M1 pro-inflammatory profile is beneficial for pathogens/tumor elimination but is detrimental for the wound healing process. In contrast, M2 anti-inflammatory profile improves chronic inflammatory diseases and regeneration. Moreover, 'chimeric' M1-M2 macrophages with mixed phenotypic features have been described in certain autoimmune diseases. Many diseases are correlated with an altered balance of M1/M2 macrophage phenotypes. Several autoimmune diseases are correlated with an increased M1/M2 ratio. Likely, a reduced frequency of anti-inflammatory M2 macrophages or prolonged activation of M1 macrophages could be implicated in the development of detrimental inflammation and autoimmunity. Additionally, it is known that the deleterious effects of reactive oxygen species produced by M1 macrophages can play a vital role by inducing the cycle of damage and healing during an autoimmune process.

Fig.1 Modulation of autoimmune diseases by monocytes and macrophages. (Ma, 2019)

M1 Macrophage and Autoimmune Diseases

M1 macrophages are a potent source of various pro-inflammatory cytokines, which are essential mediators of the effects of macrophages during the progression of autoimmune diseases. Infiltration of macrophages in the synovia is one of the most important hallmarks of RA. To be specific, unrestrained M1 polarization with incomplete M2 polarization usually leads to more severe joint pathology in AS. Accumulating studies indicate the dominance of M1 macrophages in SLE pathogenesis. Excessive M1 macrophages-related cytokines are produced by macrophages from SLE patients. Both M1 and M2 subsets are present in MS lesions. The pro-inflammatory M1 response is rapidly induced and then maintained at sites of CNS injury. M2 response is comparatively weaker and more transient. In T1D, the abnormal activation of macrophages is exemplified by the pro-inflammatory M1 phenotype of these cells, which play a crucial role in T1D pathogenesis. While pro-inflammatory M1 macrophages promote T1D development, adoptive transfer of immunosuppressive M2 macrophages reduces the onset of T1D. M1 macrophages contribute to the disruption of the intestinal epithelial barrier during IBD development. M2 polarized macrophages have been suggested as a possible collaborator in IBD immunotherapy.

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Strategies of Targeting Macrophages in RA

Similar principles for targeting macrophages for therapies may apply in autoimmune diseases. Drug targets for autoimmune diseases include stimulants for macrophage activity, which promote recruitment and activation, and subsequent macrophage-derived mediators of disease progression.

Reprogramming macrophages. Specifically, one strategy to treat autoimmune diseases is by reprogramming macrophages toward anti-inflammatory phenotypes. For example, interleukin 10 (IL-10) was shown to suppress M1 phenotypes in experimental RA and SLE.
Depletion of macrophages. Eliminating macrophages has been shown to abolish diabetes in T1D, suppress CNS damage in MS, and improve synovial inflammation in RA.
Blockade the recruitment of macrophages. The promising therapeutic targets include the IL-10, colony-stimulating factor (CSF-1) /CSF-1 receptor signaling axis, chemokine receptor (CX3CR1), monocyte chemotactic protein (MCP-1), and Bruton's tyrosine kinase for their roles in the recruitment of monocytes, macrophage polarization, and macrophage activation. Quetiapine, an antipsychotic drug, significantly reduced the recruitment and activation of macrophages in MS.
Others. Blockades against cytokines and other pro-inflammatory factors, such as IL-6, IL-15, tumor necrosis factor (TNFα), are attractive therapeutic targets such as in IBD and RA. An IL-6 blockade using an anti-IL-6 receptor antibody contributed to reduced infiltration of T cells in the central nervous system to treat MS.

Fig.2 Macrophage activity in the progression and treatment of autoimmune diseases. (Wei, 2020)

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References

Ma, W.T.; et al. The role of monocytes and macrophages in autoimmune diseases: a comprehensive review. Front Immunol. 2019, 10:1140.
Wei, H.; et al. Drug delivery to macrophages: A review of targeting drugs and drug carriers to macrophages for inflammatory diseases. Adv Drug Deliv Rev. 2020, 165-166:15-40.