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CD147 promotes MTX resistance by immune cells through up-regulating ABCG2 expression and function
Shuang Zhao1, Chen Chen, Shuang Liu
1Department of Dermatology, XiangYa Hospital, Central South University, Changsha, Hunan, People's Republic of China.
Background:
Methotrexate (MTX) is a drug used to treat psoriasis due to inducing immune cell apoptosis. However, certain patients show MTX resistant. CD147, highly expressed by psoriatic PBMCs, is assumed to regulate MTX sensitivity. The underlining mechanism is still relatively understudied.
Objective:
To understand the mechanisms of that CD147 promotes MTX resistance in immune cells.
Methods:
The expression of CD147 and ABCG2 in PBMCs from psoriatic patients, cellular apoptosis and intracellular MTX amount were measured. We also checked the cellular drug sensitivity of CHO (Chinese Hamster Ovary) cell lines with introduced CD147 and Jurkat T cells depeleted CD147. By immunoprecipitation, we detected the interaction between CD147 and ABCG2.
Results:
Both ABCG2 and CD147 are highly expressed in psoriatic PBMCs. Cultured in vitro, the PBMCs from psoriatic patients were more resistant to MTX-induced apoptosis comparing to PBMCs from healthy people. Further studies demonstrated that exogenous overexpression of CD147 in CHO cells increased ABCG2 protein level. After MTX treatment, CD147 overexpressing CHO cells showed lower apoptosis rate and lower intracellular MTX concentration. On the contrary, knockdown of CD147 by shRNA in Jurkat T cells decreased ABCG2 expression, as well as increased MTX-induced apoptosis and decreased MTX efflux. Immunoprecipitation experiment revealed that the trans-membrane domain of CD147 conferred its' interaction with ABCG2.
Conclusion:
Our study suggests a role of CD147 in regulating ABCG2 transportation of MTX in immune cells. Strategies involving targeting CD147 could be considered in clinical treatment of psoriatic patients resistant to MTX.
Insights
CD147 promotes methotrexate (MTX) resistance in psoriasis by increasing ABCG2 transporter activity, leading to reduced drug accumulation and apoptosis in immune cells. Targeting CD147 may overcome MTX resistance in psoriatic patients.
Area of Science:
- Immunology
- Dermatology
- Pharmacology
Background:
- Methotrexate (MTX) treats psoriasis by inducing immune cell apoptosis, but resistance is a clinical challenge.
- CD147 is highly expressed in psoriatic PBMCs and implicated in MTX resistance, though mechanisms are unclear.
Purpose of the Study:
- To elucidate the role of CD147 in mediating methotrexate resistance in immune cells.
Main Methods:
- Assessed CD147 and ABCG2 expression, apoptosis, and intracellular MTX in psoriatic PBMCs.
- Utilized CD147-overexpressing CHO cells and CD147-knockdown Jurkat T cells to evaluate drug sensitivity.
- Investigated CD147-ABCG2 interaction via immunoprecipitation.
Main Results:
- Psoriatic PBMCs showed higher CD147/ABCG2 expression and MTX resistance compared to healthy controls.
- CD147 overexpression in CHO cells increased ABCG2, reduced apoptosis, and lowered intracellular MTX.
- CD147 knockdown in Jurkat T cells decreased ABCG2, enhanced MTX-induced apoptosis, and reduced MTX efflux.
- The transmembrane domain of CD147 mediates interaction with ABCG2.
Conclusions:
- CD147 regulates ABCG2-mediated MTX transport in immune cells, contributing to MTX resistance in psoriasis.
- Targeting CD147 presents a potential therapeutic strategy for MTX-resistant psoriatic patients.