Targeting the Type I Interferon Pathway in Glomerular Kidney Disease: Rationale and Therapeutic Opportunities

Abstract

Type I interferons (IFNs) are immunostimulatory molecules that can activate the innate and adaptive immune systems. In cases of immune dysfunction, prolonged activation of the type I IFN pathway has been correlated with kidney tissue damage in a wide range of kidney disorders, such as lupus nephritis (LN) and focal segmental glomerulosclerosis (FSGS). Genetic mutations, such as APOL1 risk variants in conjunction with elevated type I IFN expression, are also associated with higher rates of chronic kidney disease in patients with LN and collapsing FSGS. Long-term activation of the type I IFN pathway can result in chronic inflammation, leading to kidney tissue damage, cell death, and decline in organ function. Thus, therapeutic strategies targeting type I IFN could provide clinical benefits to patients with immune dysregulation who are at risk of developing impaired kidney function. Here, we present a critical review of type I IFN signaling, the consequences of chronically elevated type I IFN expression, and therapeutic strategies targeting type I IFN signaling in the context of kidney disease.

Keywords: anifrolumab; immune dysfunction; interferon pathway; kidney disease; lupus nephritis; type I interferon.

Figure 1

Canonical type I IFN signaling pathway. GAS, gamma interferon-activated sequence; IFN, interferon; IFNAR, IFN-α receptor; IFNAR1, INFAR subunit 1; IFNAR2, IFNAR subunit 2; IRF, IFN regulatory factor; ISRE, IFN-stimulated response element; JAK1, Janus kinase 1; P, phosphate; STAT, signal transducer and activator of transcription; TYK, tyrosine kinase.

Figure 2

IFN-mediated cell damage in kidney tissue., , Kidney resident cells (i.e., podocytes, mesangial cells, and glomerular endothelial cells) are the primary producers of type I IFN in kidney tissue, which triggers inflammatory damage to the basement membrane cells. With the basement membrane weakened, immune cells can infiltrate the mesangium, drawn by cytokine production. Resident renal cells continue type I IFN production, damaging podocytes, inflaming mesangial cells, and disrupting endothelial cells. Cumulatively, the cellular damage and morphological changes to glomerular capillaries, mesangial cells, the basement membrane, and podocytes result in impaired kidney function. IFN, interferon; NET, neutrophil extracellular trap.

Figure 3

Expression of type I IFN gene signatures in the tubulointerstitial and glomerular compartments of healthy controls and patients with LN. Originally presented at EULAR 2024. FSGS, focal segmental glomerulosclerosis; GSVA, gene set variation analysis; IFN, interferon; IgA, immunoglobulin A; K-IFNGS, kidney interferon gene signature; LN, lupus nephritis.

Figure 4

Anifrolumab mechanism of action. IFN, interferon; IFNAR, IFN-α receptor; IFNAR1, INFAR subunit 1; IFNAR2, IFNAR subunit 2.