Crucial Role of AIM/CD5L in the Development of Glomerular Inflammation in IgA Nephropathy

Abstract

BackgroundIgA nephropathy (IgAN) begins with aberrant IgA deposition in glomeruli, progresses to IgM/IgG/complement codeposition, and results in chronic inflammation and glomerular damage. However, the mechanism that drives such phlogogenic cascade has been unclear. Recently, apoptosis inhibitor of macrophage (AIM) protein was shown to modulate macrophages’ function in various pathologic conditions, thereby profoundly affecting the progression of renal disorders, including AKI. A spontaneous IgAN model, grouped ddY (gddY) mouse, revealed the requirement of AIM for the overall inflammatory glomerular injury following IgA deposition.MethodsWe established an AIM-deficient IgAN model (AIM−/−gddY) using CRISPR/Cas9 and compared its phenotype with that of wild-type gddY with or without recombinant AIM administration. An IgA-deficient IgAN model (IgA−/−gddY) was also generated to further determine the role of AIM.ResultsIn both human and murine IgAN, AIM colocalized with IgA/IgM/IgG in glomeruli, whereas control kidneys did not exhibit AIM deposition. Although AIM−/−gddY showed IgA deposition at levels comparable with those of wild-type gddY, they did not exhibit glomerular accumulation of IgM/IgG complements, CD45+ leukocyte infiltration, and upregulation of inflammatory/fibrogenic genes, indicating protection from glomerular lesions and proteinuria/hematuria. Recombinant AIM administration reconstituted the IgAN phenotype, resulting in IgM/IgG/complement IgA codeposition. Neither spontaneous IgM/IgG codeposition nor disease was observed in IgA−/−gddY mice.ConclusionsAIM may contribute to stable immune complex formation in glomeruli, thereby facilitating IgAN progression. Therefore, AIM deposition blockage or disassociation from IgM/IgG may present a new therapeutic target on the basis of its role in IgAN inflammation initiation.

Multifaceted Roles of CD5L in Infectious and Sterile Inflammation

“…IgAN progression is influenced by the confluence of genetic and environmental factors and it is characterized by the presence of glomerular deposition of immune complexes, comprised of IgA1, together with IgG, IgM, and C3 of the complement system [ 59 ]. These immune deposits cause persistent inflammatory immune responses, which associate with enhanced macrophage infiltration and matrix expansion, which together lead to further glomerular damage [ 47 ]. In blood, CD5L binds to IgM pentamers, which stabilize and protect it from renal excretion [ 50 , 51 ].…”

“…Interestingly, although glomerular IgA deposition was also found in CD5L-deficient gddY mice, these animals were protected against renal injury due to the absence of IgG, IgM and C3 deposition. Thus, CD5L is essential for binding of IgM and/or IgG to previously deposited IgA to promote leukocyte infiltration, glomerular and interstitial fibrosis, extracellular matrix expansion, and increased expression of the proinflammatory genes Il-1β, IL-6, and TNF-α [ 47 ], which together enhance chronic renal damage.…”

“…Anti-inflammatory role in acute kidney injury [10], experimental autoimmune encephalomyelitis [28], and liver fibrosis [45]. Proinflammatory role in obesity [46], IgA nephropathy [47], and acute myocardial infarction [48]. [26].…”

Oxidative stress and macrophage infiltration in IgA nephropathy

“…Hence, it may facilitate IgAN progression. Blockage of AIM deposition or disassociation from IgM/IgG might therefore be a new therapeutic target in IgAN treatment [54].…”

Perspectives on how mucosal immune responses, infections and gut microbiome shape IgA nephropathy and future therapies

“…In addition, it was demonstrated that AIM was required for the overall inflammatory glomerular injury following IgA deposition in grouped ddY mice. Based on this, it was assumed that AIM might play a significant role in the formation of ICs, facilitating disease progression 162 . Therefore, blockage of AIM deposition presents to be a novel target in the treatments of IgAN.…”