Myeloid Krüppel-Like Factor 2 Critically Regulates K/BxN Serum-Induced Arthritis.

Manjusri Das,Moonmoon Deb,Vincent J. Pompili,Suman Kanji,Matthew Joseph,Reeva Aggarwal,Wael Jarjour,O. Hans Iwenofu,Dipranjan Laha,Hiranmoy Das

doi:10.3390/cells8080908

Abstract

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease, and Krüppel-like factor 2 (KLF2) regulates immune cell activation and function. Herein, we show that in our experiments 50% global deficiency of KLF2 significantly elevated arthritic inflammation and pathogenesis, osteoclastic differentiation, matrix metalloproteinases (MMPs), and inflammatory cytokines in K/BxN serum-induced mice. The severities of RA pathogenesis, as well as the causative and resultant cellular and molecular factors, were further confirmed in monocyte-specific KLF2 deficient mice. In addition, induction of RA resulted in a decreased level of KLF2 in monocytes isolated from both mice and humans along with higher migration of activated monocytes to the RA sites in humans. Mechanistically, overexpression of KLF2 decreased the level of MMP9; conversely, knockdown of KLF2 increased MMP9 in monocytes along with enrichment of active histone marks and histone acetyltransferases on the MMP9 promoter region. These findings define the critical regulatory role of myeloid KLF2 in RA pathogenesis.

Highlights

Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis affecting a significant portion of the population worldwide; in those affected it causes moderate to severe disability [1]
Ankle swelling was measured every day for 7 days and a statistically significant increase (p < 0.05) in ankle thickness in Krüppel-like factor 2 (KLF2)+/− mice compared to KLF2+/+ mice was observed (Figure 1B)
We found that expression of NFATc1, MMP13 and vATPase molecules in differentiated osteoclasts isolated from the bone marrow cells of arthritic mice was enhanced in KLF2+/− mice compared to KLF2+/+ mice (Figure 2C)

Summary

Introduction

Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis affecting a significant portion of the population worldwide; in those affected it causes moderate to severe disability [1]. Immune dysregulation is critical in the pathophysiology of RA, in which progressive destruction of synovial joints, articular cartilage, and bones are observed [2,3]. Both innate and adaptive immune responses are critical in RA pathogenesis. Various metabolic and genetic factors play important roles in RA pathogenesis [6,7]. Genetic and epigenetic factors contribute to RA pathogenesis, making it a complex syndrome with a common clinical phenotype arising from diverse pathways and operating variably in individual patients [5]

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Conclusion