mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-EAF-2503mimmun-2503Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESЭкспрессия и функция рецепторов формилированных пептидов в гранулоцитах больных ревматоидным артритомExpression and function of receptors for the formylated peptides in granulocytes of the patients with rheumatoid arthritisМохаммадА.MohammadA.

Мохаммад Афраа – аспирант лаборатории геномной инженерии

г. Долгопрудный, Московская обл.

Mohammad Afraa, Postgraduate Student, Laboratory of Genomic Engineering

Dolgoprudny, Moscow Region

afraamhmad@gmail.comhttps://orcid.org/0000-0002-1853-8365ФилинаЮ. В.FilinaYu. V.

Филина Юлия В. – научный сотрудник OpenLab «Генные и клеточные технологии» ИФМиБ

г. Казань, Республика Татарстан

Research Associate, Open Laboratory of Gene and Cell Technologies

Kazan Federal University

Julia.V.Filina@gmail.comhttps://orcid.org/0000-0002-0651-0728ЛарионоваР. В.LarionovaR. V.

Ларионова Регина В. – научный сотрудник

г. Казань, Республика Татарстан

Research Associate

Kazan Federal University

reginalarionova1993@mail.ruhttps://orcid.org/0000-0002-0584-446XАрлеевскаяМ. И.ArleevskayaM. I.

Арлеевская Марина И. – кандидат медицинских наук, старший научный сотрудник

г. Казань, Республика Татарстан

PhD (Medicine), Senior Research Associate

Kazan Federal University

marleevskaya@gmail.comhttps://orcid.org/0000-0002-8437-4389ГабдулхаковаА. Г.GabdulhakovaA. G.

Габдулхакова Аида Габдрахмановна – кандидат биологических наук, старший научный сотрудник ФГАОУ ВО «Казанский (Приволжский) федеральный университет»; старший научный сотрудник Казанской государственной медицинской академии – филиала ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Министерства здравоохранения РФ

420021, Республика Татарстан, г. Казань, ул. Парижской Коммуны, 9

Gabdoulkhakova Aida G., PhD (Biology), Senior Research Associate,Kazan Federal University; Senior Research Associate, Kazan State Medical Academy

420021, Republic of Tatarstan, Kazan, Parizhskoi Kommuny str., 9, office 506

aida.gabdoulkhakova@gmail.comФГАОУ ВО «Московский физико-технический институт (национальный исследовательский университет)»Moscow Physico-Technical InstituteФГАОУ ВО «Казанский (Приволжский) федеральный университет»Kazan Federal UniversityКазанская государственная медицинская академия – филиал ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Министерства здравоохранения РФKazan State Medical AcademyФГАОУ ВО «Казанский (Приволжский) федеральный университет»; Казанская государственная медицинская академия – филиал ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Министерства здравоохранения РФРоссияKazan Federal University; Kazan State Medical AcademyRussian Federation20220812202224611391150Copyright © Мохаммад А., Филина Ю.В., Ларионова Р.В., Арлеевская М.И., Габдулхакова А.Г., 20222022Мохаммад А., Филина Ю.В., Ларионова Р.В., Арлеевская М.И., Габдулхакова А.Г.Mohammad A., Filina Y.V., Larionova R.V., Arleevskaya M.I., Gabdulhakova A.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/2503

Рецепторы формилированных пептидов (FPR) являются важной частью врожденного иммунитета и участвуют в реализации противомикробных функций фагоцитов, таких как хемотаксис, секреторная дегрануляция и респираторный взрыв. Эти ответы фагоцитов реализуются как при остром, так и при системном хроническом воспалении. Избыточное либо постоянное высвобождение провоспалительных лигандов ведет к предактивации фагоцитов, когда последующая стимуляция вызывает более интенсивный клеточный ответ. Связывание рецептора формилированных пептидов агонистом активирует продукцию активных форм кислорода в результате запуска фосфорилирования цитоплазматических субъединиц p47phox и p67phox с последующей их транслокацией к плазматической мембране и сборкой NADPH-оксидазного комплекса. Ревматоидный артрит характеризуется дисбалансом иммунных процессов и аутоиммунной реакцией против тканей суставов. Известно, что при различных патологиях, включая ревматоидный артрит, гранулоциты продуцируют повышенные количества радикалов кислорода. Мы предполагаем, что одним из механизмов такого усиления может быть повышенная экспрессия рецепторов формилированных пептидов или компонентов сигнального пути FPR/PKC/NOX2. Целью настоящего исследования было изучение экспрессии мРНК генов рецепторов формилированных пептидов fpr1/fpr2 и FPR-зависимой продукции активных форм кислорода изолированными гранулоцитами периферической крови больных ревматоидным артритом. Объектом исследования были изолированные гранулоциты периферической крови, было проанализировано 166 и 85 образцов пациентов с ревматоидным артритом и здоровых доноров, соответственно. Продукция активных форм кислорода оценивалась с помощью люминол-зависимой хемилюминесценции. Для активации FPR1 использовали формилированный пептид fMLF в концентрации, ответ на который полностью ингибировался при предварительной обработке клеток антагонистом FPR1 N-t-boc-MLF. Активацию FPR2 осуществляли синтетическим пептидом WKYMVM, специфическим агонистом рецептора FPR2. Для больных ревматоидным артритом выявлено повышение уровня спонтанной и вызванной форболовым эфиром продукции активных форм кислорода изолированными гранулоцитами периферической крови, что отражает предактивированное состояние фагоцитов при ревматоидном артрите. Мы обнаружили, что у пациентов повышена FPR1-опосредованная продукция радикалов кислорода и экспрессия мРНК гена рецептора FPR1 в гранулоцитах крови. Усиление оксидазной функции может быть также связано с конститутивной активацией пути FPR1/PKC/NOX2 в виду положительной корреляции этих процессов. Продукция активных форм кислорода, вызванная стимуляцией рецептора FPR2, также повышена, однако ее нельзя объяснить гиперэкспрессией мРНК рецептора или активацией PKC/NOX2, что требует дальнейшего изучения. Установление механизмов регуляции сигнальных каскадов FPR1 и FPR2 может выявить новые мишени для противоревматоидной терапии.

Formyl peptide receptors (FPRs) are an important part of innate immunity involved in antimicrobial phagocyte functions such as chemotaxis, secretory degranulation, and respiratory burst. These phagocyte responses are observed in both acute and systemic chronic inflammation. Abundant or constant release of pro-inflammatory ligands leads to the pre-activation of phagocytes when subsequent stimulation induces more intense cellular response. Binding of the formyl peptide receptor with its agonist activates production of reactive oxygen species, due to triggering phosphorylation of the cytoplasmic subunits p47phox and p67phox followed by their translocation to the plasma membrane and assembly into the NADPH oxidase complex. Rheumatoid arthritis is characterized by an imbalance of immune processes and autoimmune responses against the own joint tissues. It is known that, granulocytes produce increased amounts of oxygen radicals in various pathologies, including rheumatoid arthritis. We suggest that such enhancement may be due to increased expression of formyl peptide receptors or components of the FPR/PKC/NOX2 signaling pathway. Our aim was to study the mRNA expression of fpr1/fpr2 genes and the FPR-dependent production of reactive oxygen species by isolated peripheral blood granulocytes from the patients with rheumatoid arthritis. Materials and methods. The objects of the study were isolated peripheral blood granulocytes. We analyzed, respectively, 166 and 85 samples from the patients with rheumatoid arthritis and healthy donors. The production of reactive oxygen species was assessed using luminol-dependent chemiluminescence. For FPR1 activation we used a distinct concentration of the formyl peptide fMLF: the response to it was completely inhibited by pretreatment of the cells with FPR1 antagonist N-t-boc-MLF. FPR2 activation was performed by synthetic peptide WKYMVM, a specific receptor agonist. In the patients with rheumatoid arthritis, we have revealed an increased level of spontaneous and phorbol ester-induced production of reactive oxygen species by isolated peripheral blood granulocytes, thus reflecting a pre-activated state of the phagocytes in rheumatoid arthritis. We have found the increased FPR1-mediated production of oxygen radicals and expression of mRNA of fpr1 gene in blood granulocytes of rheumatoid arthritis patients. Furthermore, the enhancement of oxidase function may be associated with constitutive activation of the FPR1/PKC/NOX2 pathway as shown by positive correlation between the processes. The production of reactive oxygen species induced by stimulation of the FPR2 receptor is also increased, but it cannot be directly attributed to overexpression of the receptor mRNA or PKC/NOX2 activation, and requires further study. Understanding the mechanisms of regulation of the FPR1 and FPR2 signaling cascades may reveal new targets for anti-rheumatoid therapy.

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The authors declare that there are no conflicts of interest present.