M2 Polarization and Pro-Fibrotic Transition of Lupus Nephritis Macrophages

Chronic inflammation is a defining feature of autoimmune diseases, such as lupus nephritis (LN), in which persistent immune activation leads to progressive kidney injury and fibrosis. Macrophages play a central role in this process because of their functional plasticity and ability to respond to environmental cues. Classically activated M1 macrophages promote inflammation through cytokines such as IL-1β, IL-6, and TNF-α, whereas alternatively activated M2 macrophages support immune regulation and tissue repair processes. However, in LN, increased infiltration of CD163⁺ M2 macrophages is associated with disease severity and fibrotic remodeling, suggesting that sustained reparative signaling may contribute to the pathology. Macrophage polarization is strongly influenced by the cytokine milieu. Canonical Th2 cytokines, including IL-4 and IL-13, drive M2 differentiation via STAT6 signaling, whereas IL-10 suppresses inflammation via STAT3 and enhances M2 marker expression. As these cytokines often coexist in chronic inflammation, we investigated whether their combined action promotes a more stable M2 phenotype than individual stimulation. Using THP-1–derived macrophages, we evaluated the role of non-canonical Th2-associated mediators, including CXCL1, CCL11, IL-6, IL-9, and TSLP, in shaping macrophage function within the LN microenvironment. To determine whether macrophages contribute directly to fibrosis, we examined the effects of TGF-β and LN patient serum on macrophage reprogramming. Renal biopsy transcriptomic analysis revealed increased expression of fibrotic markers, including vimentin, collagen I, collagen IV, and fibronectin in LN glomeruli. In vitro, TGF-β induced a dose- and time-dependent increase in fibroblast-associated markers, including α-smooth muscle actin and fibroblast-specific protein-1, indicating the acquisition of a myofibroblast-like phenotype. LN serum similarly promoted both M2 polarization and profibrotic gene expression, demonstrating that circulating lupus factors drive macrophage-mediated tissue remodeling. Finally, we propose a CRISPR-Cas9–based screening of membrane proteins to identify key receptors mediating macrophage responses to LN-associated stimuli. Together, these findings highlight macrophages as active drivers of fibrosis and provide insights into how Th2 cytokine signaling and systemic inflammatory factors contribute to progressive tissue damage in LN.

Name thesis:degree_name

Doctor of Philosophy

Discipline thesis:degree_discipline

Biology

Grantor

University of Houston

Year dc:date.issued

2026

Author dc:creator

• Biswas, Aalekhya Sharma

Advisor dc:contributor.advisor

• Mohan, Chandra

Committee members dc:contributor.committeemember

• Titus, Anto Sam Crosslee Louis Sam
• Wu, Tianfu
• Peng, Weiyi
• Lin, Chin-Yo

• M2 polarization
• Cytokine synergy
• LN serum treatment
• CSRISPRa technology

Language dc:language.iso

English

Handle dc:identifier.uri

https://hdl.handle.net/10657/21482

OAI identifier oai:identifier

oai:uh-ir.tdl.org:10657/21482