Multiparameter Analysis Identifies Heterogeneity in Knee Osteoarthritis Synovial Responses

Labinsky, Hannah; Panipinto, Paul M.; Ly, Kaytlyn A.; Khuat, Deric K.; Madarampalli, Bhanupriya; Mahajan, Vineet; Clabeaux, Jonathan; MacDonald, Kevin M.; Verdin, Peter J.; Buckner, Jane H.; Noss, Erika H.

doi:10.1002/art.41161

Cited by 24 publications

(24 citation statements)

References 44 publications

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“…Interestingly, the amount of CD4 + T cells expressing CCR5 in SM and SF of our early OA patients is comparably high as previously described in SF of patients with different forms of rheumatic joint diseases such as RA, psoriatic arthritis, and ankylosing spondylitis [ 19 , 20 ]. Nevertheless, one limitation of our study is that CD4 staining of MACS-isolated CD3 + T lymphocytes might be compounded by surface marker cleavage due to the performed enzymatic digestion, as previously described [ 21 ]. Other groups showed lower expression for CCR4 and CCR5 in end-stage OA compared to RA.…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory T cell polarization is already present in patients with early knee osteoarthritis

et al. 2021

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Background Investigating the pathophysiological mechanisms of early osteoarthritis (OA) is of utmost interest since this stage holds the strongest promise for therapeutic interventions. The aims of this study were to analyze if synovial inflammation is already present in early OA and to characterize the involved cell populations, by investigating synovial fluid (SF) and synovial membrane (SM) of early OA patients for the presence and polarization status of CD4 T cells. Methods A quantitative analysis of CD4+ T cell infiltration in SF and SM compared to peripheral blood (PB) was performed in patients with early stages of OA. We further investigated intracellular staining (ICS), surface marker, and chemokine receptor expression profiles of CD4+ T cells in SF, SM, and PB, as well as cytokine expression in native SF and PB. Matched samples of SF, SM, and PB were harvested from 40 patients with early OA at the time of surgery. Early OA was confirmed by independent surgeons intraoperatively. Samples were analyzed by flow cytometry for surface markers and cytokines, which are preferentially expressed by distinct T cell subsets (Th1, Th2, Th17, regulatory T cells). Furthermore, we analyzed native SF and PB supernatants using MACSPlex for multiple cytokine expression profiles. Results SF and SM showed a distinct infiltration of CD4+ T lymphocytes, with significantly increased expression of chemokine receptors CXCR3/CCR5, cytokine IFN-γ (preferentially expressed by Th1 cells), and CD161 (preferentially expressed by IL-17 producing Th17 cells) compared to PB. Furthermore, the percentage of CD4+ T cells polarized to Treg was significantly increased in SM compared to SF and PB. No significant differences were observed for CCR3 and CCR4 (preferentially expressed by Th2 cells), although IL-4 values were significantly higher in SM and SF compared to PB. Cytokine analysis showed comparable results between PB and SF, with only IL-6 being significantly increased in SF. Conclusions Early OA joints show already significant inflammation through CD4+ T cell infiltration, with predominant Th1 cell polarization. Inflammation seems to be driven by direct proinflammatory cell interaction. Cytokine signaling seems to be negligible at the site of inflammation in early OA, with only IL-6 being significantly increased in SF compared to PB.

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Section: Discussionmentioning

confidence: 99%

Proinflammatory T cell polarization is already present in patients with early knee osteoarthritis

et al. 2021

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“…These changes have an impact in the articular microenvironment, being crucial for the cartilage repair (33). Labinsky et al (34) stated that OA inflammation is not homogeneous, different inflammatory phenotypes exists and it may influence each patient selection criteria and treatment (28). Thus, the OA treatment requires a multifactorial approach that restrain inflammatory response and provide a pro-chondrogenic microenvironment.…”

Section: Articular Cartilage and Inflammationmentioning

confidence: 99%

“…To date, there are few clinical studies in humans considering macrophage polarization and osteoarthritis (27,34,50,52). Most of them do not access macrophage polarization and when they access, they are in vitro studies with human cells.…”

Section: Macrophages In Oamentioning

confidence: 99%

Macrophage: A Potential Target on Cartilage Regeneration

et al. 2020

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Cartilage lesions and osteoarthritis (OA) presents an ever-increasing clinical and socioeconomic burden. Synovial inflammation and articular inflammatory environment are the key factor for chondrocytes apoptosis and hypertrophy, ectopic bone formation and OA progression. To effectively treat OA, it is critical to develop a drug that skews inflammation toward a pro-chondrogenic microenvironment. In this narrative and critical review, we aim to see the potential use of immune cells modulation or cell therapy as therapeutic alternatives to OA patients. Macrophages are immune cells that are present in synovial lining, with different roles depending on their subtypes. These cells can polarize to pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, being the latter associated with wound-healing by the production of ARG-1 and pro-chondrogenic cytokines, such as IL-10, IL-1RA, and TGF-b. Emerging evidence reveals that macrophage shift can be determined by several stimuli, apart from the conventional in vitro IL-4, IL-13, and IL-10. Evidences show the potential of physical exercise to induce type 2 response, favoring M2 polarization. Moreover, macrophages in contact with oxLDL have effect on the production of anabolic mediators as TGF-b. In the same direction, type II collagen, that plays a critical role in development and maturation process of chondrocytes, can also induce M2 macrophages, increasing TGF-b. The mTOR pathway activation in macrophages was shown to be able to polarize macrophages in vitro, though further studies are required. The possibility to use mesenchymal stem cells (MSCs) in cartilage restoration have a more concrete literature, besides, MSCs also have the capability to induce M2 macrophages. In the other direction, M1 polarized macrophages inhibit the proliferation and viability of MSCs and impair their ability to immunosuppress the environment, preventing cartilage repair. Therefore, even though MSCs therapeutic researches advances, other sources of M2 polarization are attractive issues, and further studies will contribute to the possibility to manipulate this polarization and to use it as a therapeutic approach in OA patients.

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“…T cells can be broadly divided into helper T cells (T H cells), cytotoxic T cells (Tc cells), and regulatory T cells (Tregs) according to their different functions, and the first two are collectively known as effector T cells. Previous studies have shown that both CD4 + (mainly differentiated into T H cells after activation) and CD8 + T-cell subsets (mainly differentiated into Tc cells after activation) have been found at higher levels not only in synovial fluid and membranes but also in peripheral blood (Haynes et al, 2002 ; Hussein et al, 2008 ; Labinsky et al, 2020 ), which suggests that T H cells and Tc cells are involved in the pathogenesis of OA (Raphael et al, 2015 ). Specifically, OA synovial tissue exhibits increased levels of T H 1 (CD4 + IFN-γ + T cells), T H 17 (CD4 + IL-17 + T cells), and Tc (CD8 + T cells), whereas the synovial fluid has increased levels of T H 1, T H 9 (CD4 + IL9 + T cells) and T H 17 cells.…”

Section: Introductionmentioning

confidence: 99%

Immunomodulation of MSCs and MSC-Derived Extracellular Vesicles in Osteoarthritis

Zhao

Sun

et al. 2020

Front. Bioeng. Biotechnol.

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Osteoarthritis (OA) has become recognized as a low-grade inflammatory state. Inflammatory infiltration of the synovium by macrophages, T cells, B cells, and other immune cells is often observed in OA patients and plays a key role in the pathogenesis of OA. Hence, orchestrating the local inflammatory microenvironment and tissue regeneration microenvironment is important for the treatment of OA. Mesenchymal stem cells (MSCs) offer the potential for cartilage regeneration owing to their effective immunomodulatory properties and anti-inflammatory abilities. The paracrine effect, mediated by MSC-derived extracellular vehicles (EVs), has recently been suggested as a mechanism for their therapeutic properties. In this review, we summarize the interactions between MSCs or MSC-derived EVs and OA-related immune cells and discuss their therapeutic effects in OA. Additionally, we discuss the potential of MSC-derived EVs as a novel cell-free therapy approach for the clinical treatment of OA.

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Multiparameter Analysis Identifies Heterogeneity in Knee Osteoarthritis Synovial Responses

Cited by 24 publications

References 44 publications

Proinflammatory T cell polarization is already present in patients with early knee osteoarthritis

Proinflammatory T cell polarization is already present in patients with early knee osteoarthritis

Macrophage: A Potential Target on Cartilage Regeneration

Immunomodulation of MSCs and MSC-Derived Extracellular Vesicles in Osteoarthritis

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