Related Experiment Video
Updated: May 29, 2026
Murine Model of Epicutaneously-Induced Immunomodulation
Published on: June 24, 2025
Decreased collagen-induced arthritis severity and adaptive immunity in MKK-6-deficient mice
Deepa Hammaker1, Katharyn Topolewski, Meghan Edgar
1University of California San Diego at La Jolla, CA 92093, USA. dhammaker@ucsd.edu
Objective:
The MAPK kinases MKK-3 and MKK-6 regulate p38 MAPK activation in inflammatory diseases such as rheumatoid arthritis (RA). Previous studies demonstrated that MKK-3 or MKK-6 deficiency inhibits K/BxN serum-induced arthritis. However, the role of these kinases in adaptive immunity-dependent models of chronic arthritis is not known. The goal of this study was to evaluate MKK-3 and MKK-6 deficiency in the collagen-induced arthritis (CIA) model.
Methods:
Wild-type (WT), MKK-3(-/-) , and MKK-6(-/-) mice were immunized with bovine type II collagen. Disease activity was evaluated by semiquantitative scoring, histologic assessment, and micro-computed tomography. Serum anticollagen antibody levels were quantified by enzyme-linked immunosorbent assay. In vitro T cell cytokine response was measured by flow cytometry and multiplex analysis. Expression of joint cytokines and matrix metalloproteinases (MMPs) was determined by quantitative polymerase chain reaction.
Results:
MKK-6 deficiency markedly reduced arthritis severity compared with that in WT mice, while the absence of MKK-3 had an intermediate effect. Joint damage was minimal in arthritic MKK-6(-/-) mice and intermediate in MKK-3(-/-) mice compared with WT mice. MKK-6(-/-) mice had modestly lower levels of pathogenic anticollagen antibodies than did WT or MKK-3(-/-) mice. In vitro T cell assays showed reduced proliferation and interleukin-17 (IL-17) production by lymph node cells from MKK-6(-/-) mice in response to type II collagen. Gene expression of synovial IL-6, MMP-3, and MMP-13 was significantly inhibited in MKK-6-deficient mice.
Conclusion:
Reduced disease severity in MKK-6(-/-) mice correlated with decreased anticollagen antibody responses, indicating that MKK-6 is a crucial regulator of inflammatory joint destruction in CIA. MKK-6 is a potential therapeutic target in complex diseases involving adaptive immune responses, such as RA.
Insights
Mitogen-activated protein kinase kinase 6 (MKK-6) deficiency significantly reduces joint inflammation and damage in collagen-induced arthritis (CIA). This highlights MKK-6 as a key target for treating chronic inflammatory joint diseases like rheumatoid arthritis (RA).
Area of Science:
- Immunology
- Molecular Biology
- Rheumatology
Background:
- Mitogen-activated protein kinase (MAPK) kinases MKK-3 and MKK-6 are critical for p38 MAPK activation in inflammatory conditions.
- Previous research indicated MKK-3 or MKK-6 deficiency mitigates K/BxN serum-induced arthritis.
- The specific role of MKK-3 and MKK-6 in adaptive immunity-driven chronic arthritis models remained unexplored.
Purpose of the Study:
- To investigate the impact of MKK-3 and MKK-6 deficiency on collagen-induced arthritis (CIA).
- To assess the role of these kinases in adaptive immunity-mediated joint inflammation and destruction.
Main Methods:
- Wild-type (WT), MKK-3(-/-), and MKK-6(-/-) mice were subjected to collagen-induced arthritis (CIA) induction.
- Disease severity was assessed via scoring, histology, and micro-computed tomography.
- Anticollagen antibody levels, T cell cytokine responses, and joint gene expression of inflammatory mediators were analyzed.
Main Results:
- MKK-6 deficiency markedly reduced arthritis severity and joint damage compared to WT mice; MKK-3 deficiency showed an intermediate effect.
- MKK-6(-/-) mice exhibited lower pathogenic anticollagen antibody levels and reduced T cell proliferation and IL-17 production.
- Synovial expression of IL-6, MMP-3, and MMP-13 was significantly inhibited in MKK-6-deficient mice.
Conclusions:
- MKK-6 deficiency ameliorates joint inflammation and destruction in CIA, correlating with reduced anticollagen antibody responses.
- MKK-6 plays a crucial role in regulating inflammatory joint destruction within adaptive immune responses.
- MKK-6 emerges as a potential therapeutic target for complex diseases like rheumatoid arthritis (RA) that involve adaptive immunity.
