We previously reported that soluble Sema5A elevated in SLE patients and correlated with disease activity and were involved in kidney and blood system damage [17]. However, the precise role of Sema5A in the development of SLE remains unknown. Here, in this study, a significantly positive correlation was identified between Sema5A expression and the production of IL-17A in the serum of SLE patients. And we found that PlexinA1 in CD4+T cells as the most important receptor of Sema5A. Sema5A-PlexinA1 axis induced the production of IL-17A by CD4+T cells. Taken together, these results demonstrate that Sema5A plays an essential role in Th17 differentiation in SLE.
As one of the “immune semaphorins”, Sema5A involved in driving both innate and adaptive immune responses[16, 18], and it has been shown associated with the development of autoimmune diseases[11, 12, 17, 19]. It was reported that Sema5A greately promoted T cell and natural killer (NK) cell proliferation and induced secretion of Th1/Th17 proinflammatory cytokines in RA[16]. Increased co-expression of Sema5A and IL-17A in the skin of chronic spontaneous urticaria (CSU) also showed the relationship of Sema5A with IL-17A[13]. In our study, we proved that Sema5A could significantly increase Th17 (CD4+IL-17A+) cells as well as IL-17A production, but did not regulate Th1, Th2 and Treg cells. In addition to Th17 cells, it has been reported that γδT cells, CD8+ T cells, and double negative T cells (DNT, CD3+ CD4−CD8−T ) also secrete IL-17A[4]. However, Sema5A treatment could not affect CD4−IL-17A+ cells. This suggests that Sema5A may mainly promote IL-17A producation in CD4+T cells.
PlexinA1 and PlexinB3 are two major receptors of Sema5A, but the expression characteristics of these two receptors in immune cells remains unclear. We firstly found that PlexinA1 mainly expressed in CD4+T cells but not B cells, monocytes or NK cells. While PlexinB3 can rarely be detected in PBMCs. Bulk RNA sequencing data from GEO database confirmed this point. We further demonstrated that Sema5A promotes CD4+T cells differentiation into Th17 cells via connecting with PlexinA1, blocking PlexinA1 disrupts IL-17A production.
Previous studies have reported that Th17/IL-17A plays an critical role in the pathogenesis of lupus nephritis (LN) [20]. Immune complexes and other inflammatory factors stimulates renal cells producing chemokines such as CCL20, CXCL9, and CXCL10, thus recruiting Th17 cells into renal tissue to mediate tissue inflammation[21–24]. Th17/IL-17A in renal tissue can change the function and structure of renal tissue cells, and promote the inflammatory environment[25, 26]. IL-17A can also induce the expression of chemokines in renal tissue cells attracting inflammatory cells, especially neutrophils to infiltrate and further aggravate tissue damage and prevent tissue repair, ultimately leading to renal fibrosis and loss of renal function[20, 27, 28]. In addition to its role in LN, a recent study shows that IL-17A can promote the survival of long-lived plasma cells in lupus mice and increase the secretion of pathogenic autoantibodies. These plasma cells cannot be eliminated by traditional targeted B cell therapy, so targeting IL-17A may become a therapeutic target for some refractory lupus[29, 30].
The PI3K-Akt-mTOR pathway is one of the most important intracellular pathways involved in cell proliferation, growth, differentiation and survival. mTOR has recently been emerged as a key regulator of T cell proliferation and differentiation[31]. mTOR complex 1 is essential for Th1 and Th17 differentiation [32, 33]. Previous mouse studies have investigated that mTORC1 inhibitor rapamycin inhibits glomerulonephritis in lupus-prone mice by reducing Th17 cells and promoting Treg cell function[34, 35]. Clinically, the treatment of targeting T cells by inhibiting mTORC1 through rapamycin has played a significant role in the treatment of connective tissue-associated thrombocytopenia[36].Recent studies have shown that rapamycin can reverse the proliferation of Th17 cells in SLE patients and may become a target for SLE treatment[37, 38]. Interestingly, in the following mechanism study, we found that Sema5A-PlexinA1 axis activated PI3K/Akt/mTOR pathway in Th17 differentiation. Therefore, inhibiting Sema5A to reduce mTOR activation in CD4+ T cells and limit Th17 differentiation may also be a potential therapeutic target for SLE.
In conclusion, our findings suggest that Sema5A plays an important role in SLE pathology, through the induction of IL-17A by CD4+T cells. Its effect may be achieved by activating the PI3K-Akt-mTOR pathway via the PlexinA1 receptor in CD4+ T cells. This study preliminarily provides a basis for Sema5A as a potential target for SLE treatment.