Wolves, shortly after announcing Otto had injured his anterior cruciate ligament for the second time in eight months, fell to a 3-2 loss to West Ham at Molineux.
The 27-year-old Spaniard, who requires surgery on both his ACL and medial collateral ligament, now faces another lengthy spell on the sidelines.
And Nuno said on the fans' favourite, who sustained his latest injury in training on Sunday: "It's tough.
"It's tough because Jonny is a very important player, and it's the same injury which will require a lot of time.
"Now it's up to us to build his confidence because he's going to face surgery.
"There are moments of doubts, but we are here to show Jonny we support him and he's going to play for Wolves many, many times."
Otto's injury severely disrupted preparation for the clash with the Hammers, while Willy Boly also tested positive for Covid-19 and is now self-isolating.
Joao Moutinho missed out with a groin problem as well.
Nuno, though, was left angered by their defensive shortcomings against David Moyes' charges.
Jesse Lingard danced through Wolves' four-man backline to open the scoring just six minutes in, and then the Manchester United loanee was instrumental in goals for both Pablo Fornals and Jarrod Bowen.
Leander Dendoncker grabbed his first goal of the season before a brilliantly-taken strike from Fabio Silva, but Nuno's pack had given themselves too much to do.
They currently sit 14th in the Premier League with eight games remaining – nine points clear of the relegation zone.
"Yes, all the good things we did in attack were taken away by the way we approached defensive situations on counter-attacks," said Nuno.
"That was the main situation. Counter-attacks can be avoided if you use a different approach.
"So, that was the main aspect of the game. We defended poorly.
"It's something that we have to work on, and try to improve our players on that aspect. We have to find solutions.
"Offensively, I think that we were OK. We had possession of the ball and created chances, but we conceded three goals – all of them very identical.
"That did not please me. I'm not pleased, at all. The second half was much better, but not enough."
He added: "I'm angry with myself, angry with the way we deal with those situations.
"It's my responsibility. It's our mistakes which we will work on. With mistakes, we support the player and give them the solution."