OPN functions in the skin immune system
Final Report Abstract
Osteopontin (OPN) is expressed by immune cells and participates in the modulation of both adaptive and acquired immunity. We previously demonstrated functions for OPN in allergic contact dermatitis (ACD) and its murine contact hypersensitivity model (CHS), where OPN supports Th1 driven immunity through effects on dendritic cells (DC) and effector T cells. In this project we investigated regulatory functions of OPN in CHS and psoriasis-like murine skin inflammation and demonstrated novel regulatory features of OPN in cell mediated skin immunity. Chronic hand eczema which is frequently caused by allergic contact dermatitis, a delayed type allergic reaction, is treated with the retinoic acid (RA) receptor pan-agonist 9-cis-retinoic acid (9cisRA). Data on how 9cisRA modulates skin immunity is sparse. In the gut immune system retinoic acid (RA) has tolerogenic functions through effects on CD103+ DC. In the skin different DC subsets are central in the induction but also in the termination of delayed type allergy. We investigated the modulation of OPN through 9cisRA by DC and its implication in CHS. We found that DC differentiated in the presence of 9cisRA (9cisDC) have a distinct phenotype with reduced MHC-II and costimulatory molecules but upregulated co-inhibitory molecule expression. 9cisDC are compromised in the expression of major inflammatory cytokines, but highly secrete OPN. These DC efficiently convert naïve T cells into Treg cells. Interestingly, OPN-deficient (OPN-/-) 9cisDC lose their Treg inducing function, which is reestablished by substituting OPN. TNCB allergic mice treated with TNBS loaded 9cisDC showed partially inhibited CHS elicitation and had elevated numbers of Tregs in lymph nodes. Our findings propose that 9cisRA modulates DC toward a phenotype able to modulate established contact allergy through induction of Tregs. This function depends upon DC derived OPN. OPN which enhances autoimmunity is expressed in psoriasis lesions, however, its functions in psoriatic inflammation are unknown. We investigated the role of OPN in OPN deficient mice (OPN- /-) by inducing psoriasis-like inflammation through Imiquimod (IMQ). OPN-/- mice treated with IMQ showed delayed onset ear swelling and attracted less inflammatory cells to the skin. IMQ induced lymph node swelling was reduced in the absence of OPN and IMQ mediated expansion of B cells was inhibited. Further, reduction of CD4+ T cell numbers by IMQ in lymph nodes was suppressed in OPN-/- mice, with an increase in the CD4/CD8 ratio. A comparable pattern was found in spleen. Further, IMQ induced IL-17 and IL-4 expression by CD4+ lymph node T cells was reduced in OPN- /- mice. Our findings indicate that OPN is involved in the modulation of psoriasis-like inflammation by affecting lymphocyte distribution in skin and draining lymph nodes and by inducing IL-17 expression of inflammatory T cells. Concluding we find that in different inflammatory skin conditions OPN has variable functions: OPN mediates proinflammatory effects in psoriatic inflammation. However, in T cell mediated allergy, such as contact dermatitis, OPN is of role in Treg expansion eventually modulating exaggerated inflammation.
Publications
- (2018) 9-cis-Retinoic acid induces a distinct regulatory dendritic cell phenotype that modulates murine delayed-type allergy. Contact dermatitis 78 (1) 41–54
Kraus, Lea-Franziska; Scheurmann, Natalie; Frenzel, Denis F.; Tasdogan, Alpaslan; Weiss, Johannes M.
(See online at https://doi.org/10.1111/cod.12868) - Mice with heterozygous deficiency of manganese superoxide dismutase (SOD2) have a skin immune system with features of “inflamm-aging”. Arch Dermatol Res 306:143-155
Scheurmann J, Treiber N, Weber C, Renkl AC, Frenzel D, Buback F, Rueß A, Schulz G, Scharffetter-Kochanek K and Weiss JM
(See online at https://doi.org/10.1007/s00403-013-1389-7) - Osteopontin deficiency affects imiquimod-induced psoriasis-like murine skin-inflammation and lymphocyte distribution in skin, draining lymph nodes and spleen. Exp Dermatol 24:305-7 (2015)
Frenzel D, Borkner L, Scheurmann J, Singh K, Scharffetter-Kochanek K and Weiss JM
(See online at https://doi.org/10.1111/exd.12649) - Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells. EMBO J. 2017 Mar 2
Guidi N, Sacma M, Ständker L, Soller K, Marka G, Eiwen K, Weiss JM, Kirchhoff F, Weil T, Cancelas JA, Florian MC, Geiger H
(See online at https://doi.org/10.15252/embj.201694969)
