Serum amyloid A/anti-CCL20 induced the rebalance of Th17/regulatory T cells in SodA-induced sarcoidosis.

Sarcoidosis is a multisystemic granulomatous inflammation associated with Th17/regulatory T cell (Treg) polarization. As a marker of inflammation, serum amyloid A (SAA) could upregulate the expression of chemokine ligand 20 (CCL20), which induces the migration of Treg cells and Th17 cells by binding and activating thechemokine C-C receptor (CCR) 6. Our goal was to determine whether SAA/anti-CCL20 induces Th17/Treg rebalance in pulmonary sarcoidosis. The deposition of SAA- and Th17/Treg-related proteins in SodA-induced granulomas was tested using immunohistochemistry. Mice with SodA-induced sarcoidosis were treated with SAA or SAA + anti-CCL20, and then Th1/Th2 and Th17/Treg cells were detected by fluorescence-activated cell sorting (FACS) analysis. The expression of SAA/CCL20 and IL-23/IL-17A was detected by enzyme-linked immunosorbent assay (ELISA) and multiplex. Key proteins in the TGF-β/Smad signaling pathway were tested by western blot. SAA mainly plays a pro-inflammatory role by promoting the expression of CCL20 and IL-17A in bronchoalveolar lavage fluid (BALF) and serum, exacerbating this elevation of CD4+/CD8+ T cells in both mediastinal lymph nodes (LNs) and BALF, as well as proliferating Th1 in LNs in SodA-induced pulmonary sarcoidosis. In addition, SAA could also promote the proliferation of Tregs in LNs. Intriguingly, blocking of CCL20 could partially reverse the expression of Th17-related cytokine, ameliorate Th1/Th2 and Treg/Th17 bias in mice with SodA-induced pulmonary sarcoidosis, and rescue the overactivation of the TGF-β/Smad2/Smad3 signaling pathway. Anti-CCL20 may have the potential for therapeutic translation, targeting on the immunopathogenesis of pulmonary sarcoidosis.