Jessalyn Hawkins

Background: Connective tissue disease associated Interstitial lung disease (CTD-ILD) is a significant cause of morbidity and mortality in patients with systemic autoimmune diseases, particularly in systemic lupus erythematous, rheumatoid arthritis, and systemic sclerosis¹. ILD is chronic inflammation and progressive fibrosis of the lung tissue, often resulting in dyspnea, cough, and reduced pulmonary function². Approximately 30-40% of patients with ILD will develop progressive pulmonary fibrosis (PPF), which has very poor prognosis and the only definitive treatment option is lung transplant². Increasing evidence suggests that macrophage polarization plays a central role in the transition from inflammation to fibrosis in CTD-ILD³. Classically activated M1 macrophages contribute to early inflammatory signaling while alternatively activated M2 macrophages promote fibroblast activation, extracellular matrix deposition, epithelial to mesenchymal transition, and persistent fibrotic remodeling³. Understanding the molecular and cellular mechanisms regulating macrophage polarization may identify novel therapeutic strategies for CTD-ILD.

Objective: This review aims to evaluate the recent literature on the role of macrophage polarization in CTD-ILD to assess emerging therapeutic strategies targeting macrophage regulation and repolarization and immune cell crosstalk.

Search Methods: An online search of the pubmed database from the years 2021-2026 using the following words: “interstitial lung disease” “connective tissue disease” “macrophage polarization”.

Results: Recent studies demonstrate significant associations between macrophage polarization and CTD-ILD progression. Peripheral blood samples from patients with systemic sclerosis-associated ILD showed increased expression of M2 macrophage markers compared with healthy controls⁴. These data support a profibrotic macrophage phenotype in disease progression. In a separate study, the ELK4 transcription factor was identified as a potential molecular regulator of macrophage polarization, with expression being decreased in CTD and CTD-ILD patient samples⁵. ELK4 overexpression reduced M1 polarization markers in-vitro and improved pulmonary function in pulmonary fibrosis mouse models⁵. Additional studies demonstrated that immune cell crosstalk contributes to macrophage polarization. In systemic sclerosis mouse models, B-cell depletion reduced M2 macrophage differentiation and fibrosis severity, with IL-6 being the primary mediator of B-cell induced M2 polarization⁶. Furthermore, emerging evidence suggests that macrophage polarization may be reversible. In pulmonary fibrosis mouse models, early stages of the disease were associated with M1 phenotype while later stages shifted towards M2 dominance⁷.  Administration of CXCL-11 induced repolarization of M2 macrophages back toward M1 polarization⁷. Current antifibrotic therapies, like Nintedanib, may partially exert their effects through weak modulation of macrophage polarization⁸. Most current data on this topic is restricted to cell culture and animal models.

Conclusions: Macrophage polarization seems to be a critical mechanism in linking immune dysregulation and fibrosis in CTD-ILD. Molecular regulators such as ELK4, immune mediated pathways involving B-cells and IL-6, and macrophage repolarization strategies including CXCL-11 represent promising therapeutic targets for future investigation. Although the current evidence is largely preclinical these findings support continued research into macrophage directed therapies as potential approaches to slow or modify CTD-ILD progression.

Works Cited:

1. Joy GM, Arbiv OA, Wong CK, et al. Prevalence, imaging patterns and risk factors of interstitial lung disease in connective tissue disease: a systematic review and meta-analysis. Eur Respir Rev. 2023;32(167):220210. doi:10.1183/16000617.0210-2022
2. Maher TM. Interstitial Lung Disease: A Review. JAMA. 2024;331(19):1655-1665. doi:10.1001/jama.2024.3669
3. Lee JH, Jang JH, Lee S, Her M. Immunopathogenic Mechanisms in Connective Tissue Disease-Associated Interstitial Lung Disease: Incessant Loop of Immunity to Fibrosis. Int J Mol Sci. 2025;26(24):12126. doi:10.3390/ijms262412126
4. Smith V, Soldano S, Campitiello R, et al. Circulating monocytes from systemic sclerosis patients with progressive interstitial lung disease preferentially express M2 phenotype markers: in vitro and ex vivo study. RMD Open. 2025;11(4):e006135. doi:10.1136/rmdopen-2025-006135
5. Zheng Y, Fan G, Xiao Y, et al. The role of ELK4 up-regulation in macrophage polarization and its mechanism in connective tissue disease-associated interstitial lung disease. Int Immunopharmacol. 2025;163:115226. doi:10.1016/j.intimp.2025.115226
6. Numajiri H, Kuzumi A, Fukasawa T, et al. B Cell Depletion Inhibits Fibrosis via Suppression of Profibrotic Macrophage Differentiation in a Mouse Model of Systemic Sclerosis. Arthritis Rheumatol. 2021;73(11):2086-2095. doi:10.1002/art.41798
7. Kim JY, Cho DW, Choi JY, et al. CXCL11 reprograms M2-biased macrophage polarization to alleviate pulmonary fibrosis in mice. Cell Biosci. 2024;14(1):140. doi:10.1186/s13578-024-01320-7
8. Soldano S, Smith V, Montagna P, et al. Nintedanib downregulates the profibrotic M2 phenotype in cultured monocyte-derived macrophages obtained from systemic sclerosis patients affected by interstitial lung disease. Arthritis Res Ther. 2024;26:74. doi:10.1186/s13075-024-03308-7