Neutrophils are first-line immune effectors in innate immunity, employing migration, phagocytosis, and neutrophil extracellular trap (NET) formation to combat infections and mediate inflammatory responses. NET formation, the regulated extrusion of chromatin and antimicrobial proteins, is crucial for pathogen clearance but can lead to pathological inflammation when dysregulated. Cathepsins, a diverse family of proteolytic enzymes traditionally associated with lysosomal protein degradation, have emerged as key modulators of neutrophil functions. Serine cathepsins, including cathepsin G, and cysteine cathepsins, such as cathepsin C, regulate neutrophil migration, chemokine processing, and serine protease maturation, thereby orchestrating effective phagocytosis and antimicrobial activity. These enzymes also influence NET formation, linking classical lysosomal proteolysis to specialized immune responses. This review synthesizes current evidence on cathepsin-mediated regulation of neutrophil effector functions, highlighting their dual role in host defense and disease pathology, and discusses their potential as therapeutic targets for mitigating NET-driven inflammation in conditions such as autoimmune diseases, cancer metastasis, and ischemia–reperfusion injury.

Background/Objectives: Infections caused by multidrug-resistant methicillin-resistant Staphylococcus pseudintermedius (MRSP) strains are becoming increasingly common in veterinary medicine. Depending on which tet genes are present, MRSP isolates may exhibit resistance to all tetracyclines or resistance to tetracycline and doxycycline with susceptibility to minocycline. As minocycline may be a potential treatment option, our study aimed to verify this hypothesis. We have compared phenotypic resistance to tetracyclines with the presence of the tet(K), tet(L), tet(M), and tet(O) genes and conducted the molecular characterization of 50 clinical MRSP isolates of canine origin. Methods: The presence of the tet genes was determined by PCR. Molecular characterization included multilocus sequence typing (MLST) and staphylococcal cassette chromosome mec (SCCmec) typing. Results: Among the 50 examined clinical MRSP isolates, sequence type ST71 with the SCCmec II–III cassette was predominant (n = 27; 54%). Among these isolates, the tet genes were either absent or present only as the tet(K) gene, resulting in susceptibility to all tetracyclines, tetracycline and doxycycline resistance, and minocycline susceptibility. In contrast, isolates carrying the SCCmec type V cassette (n = 20; 40%) were resistant to all tetracyclines tested and belonged to ST551, ST2851 (new), ST2869 (new) and ST672. These genotypes were most often characterized by the presence of a single tet(M) gene; two genes, tet(M) and tet(K); or three genes, tet(M), tet(K) and tet(O). Notably, 28 out of 50 isolates (56%) showed minocycline susceptibility, and 19 (38%) were minocycline-susceptible and resistant to tetracycline and doxycycline. Conclusions: The obtained results indicate that genotype ST551 and its related ST2851 carry the SCCmec type V and typically contain two or even three tet genes with the tet(M) gene, which confers resistance to all tetracyclines, including minocycline. These genotypes are becoming more common in Poland, and thus, minocycline may be unsuitable for the treatment of MRSP infections in our geographical region. However, in other countries, distinct MRSP genotypes exhibiting minocycline susceptibility may predominate, such as those belonging to clonal complex 71 and carrying the SCCmec type II–III cassette. In the case of such strains, minocycline may be a therapeutic option. Therefore, it is advisable to monitor the spread of MRSP clones carrying different tet genes and exhibiting varying minocycline resistance profiles.