Serum Amyloid A Proteins Induce Pathogenic T_H17 Cells and Promote Inflammatory Disease

Abstract

Lymphoid cells that produce IL-17 cytokines protect barrier tissues from pathogenic microbes, but are also prominent effectors of inflammation and autoimmune disease. T-helper (TH17) cells, defined by RORgt-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naïve CD4 + T cells. In the nonpathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, TH17 cell behaviors vary markedly according to their environment. Here we show that SAAs additionally direct a pathogenic pro-inflammatory TH17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss-and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting TH17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies.

Mycobacterium tuberculosis stimulates IL-1β production by macrophages in an ESAT-6 dependent manner with the involvement of serum amyloid A3

“…This mechanism may play critical roles in tuberculosis associated chronic lung inflammation and tissue damage by helping Mtb establish infection in the lungs by aiding the dissemination of Mtb from the alveolar space into the lung parenchyma and granuloma formation (45). Mtb elicited SAA3 production with the involvement of ESAT-6 may also play a critical role in elicitation of Th17 immune responses in tuberculosis infection by the release of mature IL-1β by Mtb infected cells (46) as IL-17 plays critical roles in immune responses against tuberculosis infection (47). However, the significance of SAA3 in tuberculosis infection through regulation of IL-1β production in immune responses against and disease pathology of tuberculosis infection remains unclear and requires future studies with tuberculosis infection models of SAA knockout mouse strains.…”

Amyloidosis and Renal Disease in Patients with Crohn's Disease

“…In the non-pathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, Th17 cell behaviors vary markedly according to their environment [44].…”

Redundant cytokine requirement for intestinal microbiota-induced Th17 cell differentiation in draining lymph nodes

“…In the past decade, the cytokine requirements for Th17 cell differentiation have been investigated in vitro and in vivo . In vitro differentiation of mouse Th17 cells from naïve CD4 + T cells can be achieved by culturing TCR/CD28-stimulated T cells with either TGF-b and IL-6 (Bettelli et al, 2006) (Mangan et al, 2006) (Veldhoen et al, 2006), with IL-6, IL-1b, and IL-23 (Ghoreschi et al, 2010), or with IL-6 and serum amyloid A (SAA) proteins (Lee et al, 2020). These conditions induce the expression of IL-23R and RORgt in a STAT3-dependent manner (Zhou et al, 2007).…”

“…Th17 cell differentiation from naïve human cord blood CD4 + T cells can similarly be achieved with a combination of TGF-b, IL-1b, and IL-6, IL-21, or IL-23 . These cytokines have also been reported to be involved in pathogenic Th17 cell functions in the context of inflammatory conditions such as experimental autoimmune encephalomyelitis (EAE), mouse models of colitis, and IBD in humans (Bettelli et al, 2006) (Korn et al, 2007) (Langrish et al, 2005) (Kamimura et al, 2003) (Cua et al, 2003) (Sanchez-Munoz et al, 2008) (Perrier and Rutgeerts, 2011) (Lee et al, 2020). IL-23, in particular, is critical for conferring pathogenicity in several animal models, but the transcriptional and metabolic features that distinguish homeostatic from pathogenic Th17 cells remain poorly understood.…”